1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

Aliment Pharmacol Ther31, 679–692


Background  Non-alcoholic fatty liver disease affects 10–35% of the adult population worldwide; there is no consensus on its treatment. Omega-3 fatty acids have proven benefits for hyperlipidaemia and cardiovascular disease, and have recently been suggested as a treatment for non-alcoholic fatty liver disease.

Aims  To review the evidence base for omega-3 fatty acids in non-alcoholic fatty liver disease and critically appraise the literature relating to human trials.

Methods  A Medline and PubMed search was performed to identify relevant literature using search terms ‘omega-3’, ‘N-3 PUFA’, ‘eicosapentaenoic acid’, ‘docosahexaenoic acid’, ‘non-alcoholic fatty liver disease’ and ‘NAFLD’.

Results  Omega-3 fatty acids are important regulators of hepatic gene transcription. Animal studies demonstrate that they reduce hepatic steatosis, improve insulin sensitivity and reduce markers of inflammation. Clinical trials in human subjects generally confirm these findings, but have significant design inadequacies.

Conclusions  Omega-3 fatty acids are a promising treatment for non-alcoholic fatty liver disease which require to be tested in randomized placebo-controlled trials.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

Non-alcoholic fatty liver disease (NAFLD) is defined by the pathological accumulation of fat in the liver when no other explanatory disease is present: it encompasses isolated hepatic steatosis, non-alcoholic steatohepatitis (NASH) and cirrhosis. A recent review demonstrated that NAFLD affects 10–35% of the adult population worldwide;1 it is now the most common cause of liver disease in the US,2 and accounts for 11% of referrals to hepatology services.3

Non-alcoholic fatty liver disease may be regarded as the hepatic expression of the metabolic syndrome which consists of hypertension, insulin resistance, obesity and dyslipidaemia.4 The basis of this assertion is that the more facets of the metabolic syndrome that are present, the greater the chance of developing NAFLD.5, 6 Furthermore, the presence of NAFLD predicts the development of other features of the metabolic syndrome.6, 7 NAFLD is independently associated with increased cardiovascular events8 and, in the NHANES-III population based study, increased mortality.9

The pathogenesis of NAFLD is incompletely understood. Classically, it is considered to be the outcome of ‘two hits’.10 Steatosis, primarily in the form of triglyderides,11 and insulin resistance are thought to occur first. Mitochondrial dysfunction precipitating oxidative stress follows and this triggers an inflammatory and fibrogenic cascade in the primed liver.10 Whilst this provides a useful overview and incorporates the major events in the pathogenesis of NAFLD, it has been suggested that this model should be revised and that steatosis is an epiphenomenon of oxidative stress.12

Other mechanisms are emerging in the pathogenesis of NASH, notably the role of adipose tissue in the secretion of proinflammatory and prothrombotic adipocytokines, IL-6 and TNF-α13–15 and the reduced production of the adipocytokine adiponectin, a potent anti-inflammatory, insulin-sensitizing agent.16, 17

At present, there is no consensus on the treatment of NAFLD.18 Derived from an understanding of the pathogenesis of NAFLD, various treatment strategies can be identified and therapies that have been tested may be grouped accordingly (Table 1).

Table 1.   Treatment strategies in non-alcoholic fatty liver disease
Weight lossLifestyle measures102–104
Bariatric surgery109–112
Reduce insulin resistanceMetformin113–117
AntioxidantVitamin E123–125
Anti-TNFPentoxiphylline127, 128
OtherUrsodeoxycholic acid129
Angiotensin 2 antagonists130, 131
Yo Jyo Hen Shi Ko134

Currently, advice on diet and weight loss and the energetic management of any co-existing features of the metabolic syndrome form the mainstay of treatment. Studies of the dietary habits of NAFLD patients reveal that they consume less oily fish, but double the quantity of soft drinks and 27% more meat compared with the general population, and these dietary differences are associated with an increased risk of NAFLD independent of traditional risk factors.19

Omega-3 fatty acids have recently been proposed as a potential treatment for NAFLD.20 These fatty acids have proven benefit in lowering serum triglycerides and in the treatment of cardiovascular disease.21–23 Interest in their potential in the treatment of cancer, mood disorders and cognitive disorders has also emerged.24–26 There are promising data from both animal and human trials on the use of omega-3s in NAFLD. This study now reviews the potential mechanisms through which omega-3 fatty acids may be of benefit in NAFLD, and the current data supporting its use.

Omega-3 fatty acids: background and metabolism

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

Omega-3 (N-3) fatty acids are essential, polyunsaturated fatty acids (PUFAs), i.e. they cannot be synthesized in vivo. In diet, large quantities are found naturally in fish oil, flaxseed and some nuts. They derive from α-linolenic acid and mainly occur as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are both anti-inflammatory.27 These are then converted to active metabolites, in particular, molecules known as resolvins and protectins. These recently discovered lipid products are yet to be fully characterized, but are thought to mediate, at least in part, the anti-inflammatory effect of omega-3 fatty acids.28 The other key group of PUFAs, N-6 fatty acids, are found predominantly in grain. They derive from linolenic acid and their primary metabolite, arachadonic acid, is proinflammatory and prothrombotic.

N-6 and N-3 fatty acids (PUFAs) are competitively metabolized by the same pathway. It has been suggested that the ratio of N-6 to N-3 should be approximately 3:1; however, because the modern diet is rich in N-6 foods, it can be as high as 15:1.29, 30 In NAFLD, a biopsy-based study showed that the N-6:N-3 ratio correlated significantly with the quantity of hepatic triglycerides.30 Although some diseases, including breast cancer and asthma, may be associated with a higher N6:N3 ratio, large trials have shown that reduction in cardiovascular risk is linked to the total amount of N-3 fatty acids rather than the N-6:N-3 ratio.31 Similarly, we believe this to be the case in NAFLD and it is now established that a low total N-3 level is found in NAFLD, and this is associated with steatosis, increased oxidative stress and NASH.11, 32–34

Omega-3 regulation of hepatic gene expression

Omega-3 fatty acids are key regulators of hepatic gene transcription, with peroxisome proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein-1 (SREBP-1) being best known. These have diverse effects on carbohydrate and lipid metabolism (Figure 1) and may act like hydrophobic hormones: i.e. upon ligand binding and activation, they bind to and alter the function of specific response elements in target genes.35, 36


Figure 1.  Effects of omega-3 fatty acids on hepatic gene transcription.

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Peroxisome proliferator-activated receptor alpha.  PPARα is a transcription factor known to reduce plasma lipids (the basis of fibrates)37 and increase mitochondrial beta oxidation.38 Two studies employing a murine model of NASH demonstrated that infusion of a PPARα agonist can prevent steatohepatitis and reverse established disease.39, 40 Omega-3s are potent activators of PPARα, which upregulate several genes associated with fatty acid and lipid metabolism that stimulate fatty acid oxidation.29, 35, 41–44 Interestingly, in addition to improvements in steatosis, there may be an independent, anti-inflammatory effect via PPARα-mediated suppression of TNF-α and IL-6.43, 45

Sterol regulatory element-binding protein-1.  There are three isoforms of SREBP: 1a,1c and 2. SREBP-1a is a potent activator of all genes under SREBP regulation; SREBP-1c primarily influences genes involved in fatty acids synthesis; SREBP-2 is implicated in cholesterol synthesis.46 For simplicity, 1a and 1c will be considered jointly as SREBP-1.

Sterol regulatory element-binding protein-1 plays an important role in insulin resistance and is also a key regulator of fatty acid synthesis.47 Levels are elevated in response to high insulin and glucose concentrations by increasing the production of its precursor.46–48 To form mature SREBP-1, the molecule requires to undergo two post-translational processes – proteolytic processing and proteasomal degradation in the golgi apparatus.38 Following this, the mature SREBP-1 is transported to the nucleus where, by binding to sterol regulatory elements in the promoter areas of genes, it stimulates increased de novo lipogenesis48, 49 and glycolysis.35 Hence, over-expression of SREBP-1 results in accumulation of triglycerides in the liver.50 Target genes for SREBP-1 include glucokinase, the intracellular enzyme which is the rate limiting step for glycolysis.48 Omega-3s reduce the amount of mature SREBP-1 available in the nucleus51 and thereby inhibit the downstream stimulatory effects of insulin35 so reducing de novo lipogenesis.52 This effect may be mediated by reducing the effective half life of SREBP-1 mRNA.53 SREBP-1 has been shown to be suppressed by omega-3 fatty acids in both cell culture and animal models.49, 54–56

Thus, the effect of omega-3 fatty acids on PPARα is to increase hepatic beta oxidation and lipid catabolism, whilst its effect on SREBP-1 is to reduce endogenous lipid production.

Others.  PPARγ, like PPARα, is a nuclear receptor involved in lipid metabolism, being primarily expressed in macrophages and adipose tissue. It is a regulator of adipose tissue metabolism, increases peripheral insulin sensitivity and is a therapeutic target for the thiazolidinediones. Omega-3 fatty acids are also ligands for PPARγ.36 In a study of healthy humans, omega-3 supplementation has been shown to increase fat oxidation and increase insulin sensitivity.57 Another study found that omega-3 improved peripheral insulin, but increased hepatic insulin resistance.58

In addition to PPARs, there are three other nuclear hormone receptors involved in fat metabolism: liver X receptor (LXR), farnesoid X receptor (FXR) and hepatocyte nuclear factor-4α (HNF-4α). The effect of omega-3 fatty acids on these receptors and their inter-relations are complex and still being elucidated.

Liver X receptors regulate fatty acid and cholesterol transport and metabolism.59, 60 These effects are mediated, at least in part, by enhancing genes involved in bile salt synthesis and by inhibiting intestinal cholesterol absorption. Interestingly LXR also increases SREBP-1 expression, thus promoting de novo triglyceride synthesis. Although it initially appeared that LXR expression was suppressed by omega-3s, there is now evidence that its expression remains unaffected.61

Hepatocyte nuclear factor-4α, which is implicated in the development of juvenile onset type 2 diabetes, plays an important role in lipoprotein production, increases l-pyruvate kinase and glucokinase expression in the liver.62 HNF-4α is stimulated by saturated fatty acids and inhibited by omega-3 fatty acids.59 Thus, omega-3 fatty acids inhibit glucose flux in the hepatocyte and downregulate hepatic lipogenesis in part through regulation of HNF-4α expression.

Farnesoid X receptor controls bile salt synthesis by inhibiting bile synthesis enzymes and bile salt export pump. It also reduces hepatic triglycerides by inducing PPARα and by inhibiting SREBP-1; the latter effect is mediated by enhancing the transcription of short heterodimer partner.63 Omega-3 fatty acids are known to upregulate FXR.64

Another potential mechanism of omega-3s is inhibition of glycolysis by suppressing carbohydrate regulatory element-binding protein (ChREBP) and through this inhibiting l-pyruvate kinase.35, 65, 66 ChREBP has been shown to be linked to hepatic steatosis and insulin resistance, and in animal models, blocking this molecule has improved steatosis and increased insulin sensitivity.67 Fatty acid synthase (FAS), another suppressor of glucokinase, is similarly inhibited by omega-3 fatty acids.68, 69

Effect of omega-3 on cell membrane composition

Omega-3 fatty acids have important properties as membrane stabilizers and can alter cell membrane fluidity.70 Fatty acids are an essential constituent of the cell membrane, where they modulate the action of membrane-bound transporters and enzymes. Dietary intake has been shown to influence hepatocyte membrane phospholipids composition and function.71 Low levels of omega-3 in skeletal muscle phospholipids are associated with insulin resistance.72 They also play an important role in modifying intracellular messengers and altering intracellular functions.73 In a cell-based study, it was shown that EPA increased the oxidation of endogenous fatty acids, and intracellular carnitine palmitoyltransferase-1 (CPT-1) levels, but did not inhibit lipogenesis. It also confirmed that they altered membrane composition and increased the amount of EPA in the adipocyte mitochondrial membrane.74

Animal models

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

The potentially beneficial effects of omega-3 fatty acids in NAFLD are supported by findings from animal studies and summarized in Figure 2. Several animal models have been used in NAFLD studies, although none truly replicates the pathogenesis and metabolic milieu of NAFLD/NASH.75 In addition, the quantity of omega-3 fatty acids used in these studies is in excess of that used in human studies: omega-3s generally constituted 5–20% of the animal’s total dietary intake.


Figure 2.  NAFLD pathogenesis with regards to potential omega-3 fatty acids targets.

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As would be expected from the cardiovascular trials, omega-3 treatment reduces plasma lipids.76–78 Omega-3 fatty acids have also consistently been shown to reduce hepatic steatosis in murine models. In a model of parenteral nutrition, which results in universal steatosis and abnormal liver enzymes, omega-3s protected the murine liver against hepatic steatosis, when given prophylactically.79 The same group found omega-3 fatty acids also improved established hepatic steatosis in leptin-deficient obese mice.80 This finding is confirmed in numerous other studies for both omega-3 mix, and EPA and DHA alone.76–78, 81–85

In addition to improvement in hepatic steatosis, ob/ob mice treated with omega-3s have demonstrated markedly decreased SREBP-1 levels with consequent reduced expression of lipogenic genes such as FAS in the liver.83 The suppression of SREBP-1 and genes involved in lipid metabolism have been confirmed in other publications.76, 78, 81, 85

In a further series of experiments using leptin-deficient ob/ob mice, it has been shown that, in addition to confirming reduced liver triglyceride content with omega-3 supplementation, these animals had lowered plasma alanine aminotransferase (ALT) levels and improved hyperglycaemia and hyperinsulinaemia, in a manner hypothesized to be related to PPARα, although this was not measured.83 The increase in PPARα in response to omega-3 supplementation was later confirmed elsewhere.76, 84, 86 In a study in Fischer rats, a group fed fish oil had reduced hepatic triglycerides and blunting of the normal postprandial decline in fatty acid degradation genes, such as PPARα, and the normal postprandial rise in triglyceride synthesis genes such as SREBP-1.87

Omega-3s have also been shown to improve insulin sensitivity. In one series of experiments, there was increased expression of insulin-sensitizing genes in adipose tissue and liver (e.g. PPARγ) in mice treated with omega-3. Improved insulin sensitivity was confirmed by insulin tolerance testing. There was also increased expression of resolvins and protectins. These are omega-3-derived mediators which are insulin-sensitizing and anti-steatotic. It was hypothesized that this might contribute to how omega-3 fatty acids exert their effect, as in this study, SREBP-1 expression, TNF-α levels and IL-6 remained unchanged.82

Recently, it has been reported that rats fed a high-fat diet supplemented with fish oil were protected against the severe hepatic steatosis and increased lipid peroxidation seen in a group fed the same diet without omega-3 supplementation.88 The oxidative stress and mitochondrial function of rats fed a high-fat diet enriched with omega-3 were similar to those observed in the controls. Furthermore, there is evidence from other studies that omega-3 supplementation reduces reactive oxygen species (ROS).76

The anti-inflammatory effects of omega-3 fatty acids are poorly characterized, but thought to be partly mediated via PPARα.89 A murine model of NAFLD showed that omega-3 fatty acids reduced leucotriene and prostaglandins.90 They also modulate the inflammatory response with reduced TNF-α.77, 84, 91, 92 Adiponectin, a powerful insulin-sensitizing agent produced in adipose tissue, is increased in animals treated with omega-3 fatty acids.77, 82, 93

In a rat model, insulin resistance and central obesity were associated with increased TNF-α, decreased PPARα and adiponectin. Animals demonstrated hepatic insulin resistance and this resulted in hepatic steatosis and fibrosis. Omega-3 supplementation restored PPARα and adiponectin levels, reduced TNF-α and ameliorated hepatic steatosis and the degree of liver injury.84

Evidence from human trials

  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

To date, three published clinical trials have investigated the therapeutic effects of omega-3s in patients diagnosed with NAFLD. Two other studies have examined the effects of omega-3s in relation to serum adiponectin levels and hepatic steatosis. These trials were of variable duration and used differing preparations of omega-3 fatty acids; the optimal composition, dose and duration of omega-3 therapy have not yet been delineated. All reported good patient compliance with side effects being infrequent. A summary of the trial’s designs, results and methodology is presented in Tables 2 and 3.

Table 2.   Summary of trial design and results
StudyNInclusion criteriaTreatment armTreatment (n)Control armControl (n)DurationMain results of treatment
  1. LFT, liver function tests; ALT, alanine aminotransferase; AST, aspartate transaminase; PUFA, polyunsaturated fatty acids; NASH, non-alcoholic steatohepatitis; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; MRS, magnetic resonance spectroscopy.

  2. * The composition of the PUFA mix was not specified.

  3. † This was a PUFA mixture of 51.4% C20:5, 23.9% C22:6, 2.8% C20:1 and 2.5% C22:0; C16:0 and C16:1 were <2%.

Capanni et al.9456Fatty liver on ultrasound1 g PUFA daily (EPA:DHA ratio: 0.9:1.5)42Observation only1412 monthsReduced hepatic steatosis on the US
 PUFA group (baseline vs. after treatment)
  15 Severe fatty liver vs. 6 severe, 6 moderate and 3 mild
  19 Moderate fatty liver vs. 6 moderate, 8 mild and 5 no fatty liver
  8 Mild fatty liver vs. 3 mild, and 5 no fatty liver.
 Control group
  At baseline 6 severe, 5 moderate and 3 mild fatty liver. No change at end of study
Mean change in serum biochemistry in PUFA vs. Observation group:
 LFTs: ALT: −4 IU/L (s.d. 8) vs. +4 (s.d. 5) (P < 0.002); AST: −2 IU/L (s.d. 4) vs. +4 (s.d. 6) (P < 0.003); γGT: −4 IU/L (s.d. 13) vs. +4 (s.d. 12) (P < 0.03)
 Triglycerides: −46 mg/dL (s.d. 88) vs. +9 (s.d. 27) (P < 0.02)
 Fasting glucose: −6 mg/dL (s.d. 14) vs. +4 (s.d. 9) (P < 0.02)
Spadaro et al.9536Fatty liver on ultrasound2 g PUFA daily*18Dietary advice only186 monthsThe US findings: steatosis grade (0/1/2/3 (%)). In the PUFA group: 0/0/39/61 at baseline vs. 33/22/44/0 after treatment. In the observation group: 0/0/44/56 at baseline vs. 0/11/50/39 at study end
Serum biochemistry (baseline vs. after treatment) in the PUFA group
 LFTs: ALT: 56.6 U/L (s.d. 24) vs. 39.5 (s.d. 14) (P < 0.01); AST: 31.5 U/L (s.d. 13) vs. 28 (s.d. 9) (N.S.); γGT: 39.3 U/L (s.d. 26) vs. 28.0 (s.d. 17) (P < 0.05)
 Triglycerides: 147.4 mg/dL (s.d. 41) vs. 110 (s.d. 39) (P < 0.01)
 HOMA-IR: 3.5 (s.d. 2.0) vs. 2.8 (s.d. 1.7) (P < 0.05)
 TNF-α: 3.3 pg/mL (s.d. 0.5) vs. 2.7 (s.d. 0.5) (P < 0.05)
There was no significant change in serum biochemistry (baseline vs. after treatment) in the observation group
Tanaka et al.9623NASH on liver biopsy2.7 g EPA daily23No controlN/A12 monthsHepatic steatosis grade on the US changed from 2.1 ± 0.9 at baseline to 1.6 ± 1.1 after treatment (P = 0.004)
Serum biochemistry (baseline vs. after treatment)
 LFTs: ALT: 79 IU/L (s.d. 36) vs. 50 (s.d. 20) (P = 0.002); AST: 50 IU/L (s.d. 17) vs. 36 (s.d. 15) (P = 0.001)
 Triglycerides: 201 mg/dL (s.d. 90) vs. 183 (s.d. 103) (N.S.)
 Total cholesterol: 219 mg/dL (s.d. 44) vs. 206 (s.d. 38) (P = 0.039)
 HOMA-IR: 4.0 (s.d. 2.0) vs. 3.4 (s.d. 2.4) (P = N.S.)
 Plasma thioredoxin: 30 ng/mL (s.d. 15) vs. 22 (s.d. 6) (P = 0.036)
Change in histological grade (baseline vs. after treatment):
 Steatosis: 2.4 (s.d. 0.5) vs. 1.7 (s.d. 0.5)
 Fibrosis: 1.7 (s.d. 1.1) vs. 0.7 (s.d. 0.5)
 Lobular inflammation: 2.1 (s.d. 0.7) vs. 1.1 (s.d. 0.7)
 Ballooning: 1.6 (s.d. 0.5) vs. 0.9 (s.d. 0.4)
 NAS: 6.1 (s.d.1.3) vs. 3.7 (s.d. 1.4)
Vega et al.9816Previous elevated liver fat on MRS9 g PUFA daily†16No controlN/A8 weeksPlasma triglyceride level pre-treatment 117 mg/dL; after PUFA 74 mg/dL (P < 0.03)
Liver fat content 7.9% pre-treatment; 8.0% after PUFA
Itoh et al.7752Obesity1.8 g EPA daily26Dietary advice only263 monthsPlasma triglycerides (means pre- and post-treatment): 166 mg/dL (S.E. 18.3) and 128 (S.E. 10.9) in the EPA group vs. 159 mg/dL (S.E. 13.3) and 151 (S.E. 12.4) in controls (P < 0.05)
Serum adiponectin (means pre- and post-treatment): 4.65 μg/mL (S.E. 0.64) and 7.42 μg/mL (S.E. 0.52) in the EPA group vs. 5.51 μg/mL (S.E. 1.04) and 5.86 μg/mL (S.E. 0.71) in controls (P < 0.01)
Table 3.   Summary of trial methodology
StudyPrimary diagnosisDesignRandomizedSample size calculationPlaceboControl armPrimary outcome measuresHistology
  1. NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease, MR, magnetic resonance.

Capanni et al.94NAFLDOpen labelNo Comparison group self-selectedYesNoObservation onlyAppearance of the liver on ultrasoundNo
Spadaro et al.95NAFLDOpen labelYes Random number samplingYesNoDietary advice onlyAppearance of the liver on ultrasound, transaminasesNo
Tanaka et al.96NASHOpen labelNoNoNoN/AAppearance of the liver on ultrasound, transaminases, liver histologyYes
Vega et al.98Fatty liver on MR spectroscopyOpen labelNoNoNoN/APlasma and hepatic triglyceridesNo
Itoh et al.77ObesitySingle blindYesNoNoDietary advice onlySerum adiponectinNo

The first trial94 was an open-label study of 56 patients with fatty liver on ultrasound and a clinical diagnosis of NAFLD. Of these patients, 42 were treated with 1 g of N-3 PUFA daily. The 14 patients who declined treatment acted as a comparison group: they did not receive any other intervention. Groups shared similar baseline clinical and ultrasonic characteristics. The primary outcome measure of the study was the appearance of the liver on B mode ultrasound and duplex Doppler (undertaken by one ultrasonographer).

All participants completed the trial. After 12 months, there was a significant reduction in hepatic steatosis determined on ultrasound in the treatment group, with improvements in 64% of participants (either less steatosis or normal appearances). In contrast, there was no change in the prevalence or severity of steatosis in the comparator group. There were also significant improvements in serum liver function tests, fasting blood glucose and serum triglycerides only in the intervention group, while the N6:N3 ratio was reduced.

In summary, this trial provided encouraging evidence for omega-3s as a potential therapy in NAFLD, but there were design weaknesses, notably, the absence of blinding and randomization, and the use for comparison of a self-selected small group consisting of those patients who had declined entry to the treatment arm.

The second trial95 involved 40 patients with a clinical diagnosis of NAFLD. Following recruitment, participants were assigned to two groups on a 1:1 basis using random sampling numbers, but neither participants nor investigators were blinded. Both groups received the same dietary advice. Those in the treatment arm also received 2 g of PUFA daily for 6 months. Outcome measurements included fatty liver as assessed by abdominal ultrasound, liver function tests and insulin resistance assessed by homeostasis model assessment-insulin resistance (HOMA-IR). The ultrasonographer was blinded to the treatment of the patient. The groups were satisfactorily matched for age, gender, body mass index and baseline insulin resistance.

Two patients dropped out in each arm leaving 36 to complete the trial. Outcome measures were compared pre- and postintervention. Results showed improved serum biochemistry with reduction in plasma triglycerides, γGT and ALT in the PUFA group after treatment. There was no significant difference in serum biochemistry after 6 months in the control group. The intervention group also displayed improved insulin sensitivity and decreased TNF-α. Ultrasound grading of liver fat improved in 83% of the intervention group with 33% reverting to normal appearances, whereas in the control group, 72% of participants’ steatosis scores remained unchanged and none reverted to normal.

Although this trial was superior to the first study in that there was randomization with the establishment of a control group, there were still design weaknesses – specifically lack of placebo, and the nonblinding of participants and investigators.

The most recent trial96 included 23 patients with NASH confirmed on liver biopsy who received 2.7 g of EPA daily for 12 months. There was no control group and no sample size calculation in what was described as a pilot trial; seven participants agreed to have a repeat biopsy at the end of the treatment period. All patients had previously received dietary advice and other medications remained unchanged throughout the study. Outcome measures were serum liver biochemistry, appearance on ultrasound and liver histology. Histology was graded using the NAFLD activity score.

All patients completed the trial. At the end of the study period, the mean steatosis grade on ultrasound had improved significantly. In 6 of the 7 patients who underwent repeat biopsy, there was reduced steatosis, inflammation and fibrosis. ALT and aspartate aminotransferase significantly improved; cholesterol and free fatty acids were significantly reduced. There was no change in serum triglycerides, high-density lipoproteins, fasting blood sugar, adiponectin levels or insulin resistance. Serum TNF-α improved, but this did not reach statistical significance. Thioredoxin, a molecule associated with hepatic oxidative stress,97 also improved.

This was the only human study of omega-3 fatty acids to have histological data, which are generally regarded as the most valid outcome measure. Whilst this trial provides further evidence of the benefits of using omega-3 fatty acids in NAFLD, the absence of randomization, controls and blinding, the small sample and the lack of power rule out reliable conclusions.

A fourth study98 involved a 8-week treatment with 9 g of fish oil in 17 patients who had previously been enrolled and demonstrated to have elevated hepatic triglycerides on liver magnetic resonance spectroscopy as part of the Dallas Heart Study.99 There was a 4-week run in period with placebo designed to assess compliance. One patient withdrew from the trial leaving 16 patients in the final analyses. Causes of liver disease other than NAFLD were not excluded and alcohol intake was not reported. It remains unclear whether study participants received any other interventions such as diet or lifestyle advice. Primary outcome measures were plasma and hepatic triglyceride levels, the latter assessed on magnetic resonance spectroscopy.

This study demonstrated that omega-3 fatty acids supplementation altered the fatty acid constituent of plasma triglycerides, which were themselves significantly reduced as a result of treatment. Very low-density lipoproteins were also reduced, but hepatic triglycerides were not. The authors could not explain their results with reference to the mechanisms currently believed to regulate hepatic triglyceride levels. It could be hypothesized that this result arose from it being a small, short trial, with an atypical sample (predominantly females and African Americans) whose diagnosis might not have been NAFLD anyway. There was also a skewed baseline hepatic triglyceride content and the dose of PUFA was much higher than that used in other trials.98

Finally, a 2007 study examined the effect of EPA on serum adiponectin levels in 52 obese Japanese patients all of whom fulfilled criteria for the metabolic syndrome.77 This was a single blinded pilot trial with patients randomized to receive either dietary advice only, or 1.8 g of EPA in addition to dietary advice for 3 months. There was no other change to participant’s medication during the trial period. This study demonstrated that EPA supplementation increased plasma adiponectin in the treatment group, but markers of NAFLD were not reported.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

Non-alcoholic fatty liver disease is a common and growing problem worldwide.1, 99–100 Although frequently asymptomatic and relatively benign, NAFLD has the potential to progress to cirrhosis. Cirrhosis, when decompensated, has a poor prognosis.101

Currently, the mainstays of treatment are dietary advice, help and encouragement to lose weight, and exercise, and energetic treatment of co-existing disorders, especially, Type 2 diabetes and hypertension. Treatment strategies to date may be grouped into those that address weight loss, improve insulin sensitivity, are antioxidant, anti-TNF or have other mechanisms of action, but none has become an established intervention.

Omega-3 fatty acids have been suggested as a treatment for NAFLD.20 They have several potential mechanisms of action, the most important being to alter hepatic gene expression, thereby switching intracellular metabolism from lipogenesis and storage to fatty acid oxidation and catabolism. There is also evidence that they improve insulin sensitivity, are anti-inflammatory and reduce TNF levels thus offering several potential therapeutic mechanisms.

Animal studies have shown promise with reduction in hepatic steatosis, improved insulin sensitivity, reduced inflammation and oxidative stress consistently reported. In humans, preliminary clinical trials have confirmed this potential with three of the four studies reporting a reduction in hepatic steatosis on imaging, increased insulin sensitivity and improved serum liver function tests. They have also confirmed the tolerability of omega-3 fatty acids, which is an important factor in a disorder which is usually asymptomatic. To date, the trials have all been open-label and none has employed a prospective, randomized, blinded, placebo-controlled, adequately powered trial methodology to submit these promising preliminary findings to proper scientific rigour. Such studies are now urgently required.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References

Declaration of personal interests: None. Declaration of funding interests: There has been no financial support received for this study and the authors have nothing to disclose.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Omega-3 fatty acids: background and metabolism
  5. Animal models
  6. Evidence from human trials
  7. Conclusions
  8. Acknowledgements
  9. References
  • 1
    Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty liver disease (NAFLD). Ann Hepatol 2009; 8(Suppl. 1): S48.
  • 2
    McCullough AJ. Update on nonalcoholic fatty liver disease. J Clin Gastroenterol 2002; 34: 25562.
  • 3
    Byron D, Minuk GY. Clinical hepatology: profile of an urban, hospital-based practice. Hepatology 1996; 24: 8135.
  • 4
    Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus, Group. The metabolic syndrome – a new worldwide definition. Lancet 2005; 9491: 105962.
  • 5
    Prashanth M, Ganesh HK, Vima MV, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Assoc Physicians India 2009; 57: 20510.
  • 6
    Fan JG, Li F, Cai XB, Peng YD, Ao QH, Gao Y. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J Gastroenterol Hepatol 2007; 22: 108691.
  • 7
    Hanley AJ, Williams K, Festa A, Wagenknecht LE, D’Agostino RB Jr, Haffner SM. Liver markers and development of the metabolic syndrome: the insulin resistance atherosclerosis study. Diabetes 2005; 54: 31407.
  • 8
    Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 10: 157984.
  • 9
    Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol 2008; 103: 226371.
    Direct Link:
  • 10
    Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998; 114: 8425.
  • 11
    Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007; 46: 108190.
  • 12
    Serviddio G, Sastre J, Bellanti F, Vina J, Vendemiale G, Altomare E. Mitochondrial involvement in non-alcoholic steatohepatitis. Mol Aspects Med 2008; 29: 2235.
  • 13
    Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 1999; 892: 892.
  • 14
    Greenfield V, Cheung O, Sanyal AJ. Recent advances in nonalcholic fatty liver disease. Curr Opin Gastroenterol 2008; 24: 3207.
  • 15
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796808.
  • 16
    Pagano C, Soardo G, Esposito W, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol 2005; 152: 1138.
  • 17
    Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 77283.
  • 18
    Moseley RH. Therapy for nonalcoholic fatty liver disease. J Clin Gastroenterol 2008; 42: 3325.
  • 19
    Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 2007; 47: 7117.
  • 20
    Xin YN, Xuan SY, Zhang JH, Zheng MH, Guan HS. Omega-3 polyunsaturated fatty acids: a specific liver drug for non-alcoholic fatty liver disease (NAFLD). Med Hypotheses 2008; 71: 8201.
  • 21
    McKenney JM, Sica D. Role of prescription omega-3 fatty acids in the treatment of hypertriglyceridemia. Pharmacotherapy 2007; 27: 71528.
  • 22
    Jacobson TA. Secondary prevention of coronary artery disease with omega-3 fatty acids. Am J Cardiol 2006; 98(4A): 6170.
  • 23
    Von Schacky C. n-3 fatty acids and the prevention of coronary atherosclerosis. Am J Clin Nutr 2000; 71(1 Suppl.): 224S7S.
  • 24
    Wendel M, Heller AR. Anticancer actions of omega-3 fatty acids – current state and future perspectives. Curr Med Chem Anticancer Agents 2009; 9: 45770.
  • 25
    Appleton KM, Rogers PJ, Ness AR. Is there a role for n-3 long-chain polyunsaturated fatty acids in the regulation of mood and behaviour? A review of the evidence to date from epidemiological studies, clinical studies and intervention trials. Nutr Res Rev 2008; 21: 1341.
  • 26
    Dyall SC, Michael-Titus AT. Neurological benefits of omega-3 fatty acids. Neuromolecular Med 2008; 10: 21935.
  • 27
    Stulnig TM. Immunomodulation by polyunsaturated fatty acids: mechanisms and effects. Int Arch Allergy Immunol 2003; 132: 31021.
  • 28
    Serhan CN. Novel eicosanoid and docosanoid mediators: resolvins, docosatrienes, and neuroprotectins. Curr Opin Clin Nutr Metab Care 2005; 8: 11521.
  • 29
    El-Badry AM, Graf R, Clavien PA. Omega 3 – Omega 6: what is right for the liver? J Hepatol 2007; 47: 71825.
  • 30
    Vuppalanchi R, Cummings OW, Saxena R, et al. Relationship among histologic, radiologic, and biochemical assessments of hepatic steatosis: a study of human liver samples. J Clin Gastroenterol 2007; 41: 20610.
  • 31
    Griffin BA. How relevant is the ratio of dietary n-6 to n-3 polyunsaturated fatty acids to cardiovascular disease risk? Evidence from the OPTILIP study. Curr Opin Lipidol 2008; 19: 5762.
  • 32
    Videla LA, Rodrigo R, Araya J, Poniachik J. Oxidative stress and depletion of hepatic long-chain polyunsaturated fatty acids may contribute to nonalcoholic fatty liver disease. Free Radic Biol Med 2004; 37: 1499507.
  • 33
    Araya J, Rodrigo R, Videla LA, et al. Increase in long-chain polyunsaturated fatty acid n − 6/n − 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci 2004; 106: 63543.
  • 34
    Allard JP, Aghdassi E, Mohammed S, et al. Nutritional assessment and hepatic fatty acid composition in non-alcoholic fatty liver disease (NAFLD): a cross-sectional study. J Hepatol 2008; 48: 3007.
  • 35
    Jump DB. N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr Opin Lipidol 2008; 19: 2427.
  • 36
    Marx N, Duez H, Fruchart JC, Staels B. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells. Circ Res 2004; 94: 116878.
  • 37
    Watts GF, Dimmitt SB. Fibrates, dyslipoproteinaemia and cardiovascular disease. Curr Opin Lipidol 1999; 10: 56174.
  • 38
    Jump DB, Botolin D, Wang Y, Xu J, Demeure O, Christian B. Docosahexaenoic acid (DHA) and hepatic gene transcription. Chem Phys Lipids 2008; 153: 313.
  • 39
    Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology 2003; 38: 12332.
  • 40
    Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 2004; 39: 128696.
  • 41
    Xu HE, Lambert MH, Montana VG, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999; 3: 397403.
  • 42
    Pawar A, Jump DB. Unsaturated fatty acid regulation of peroxisome proliferator-activated receptor alpha activity in rat primary hepatocytes. J Biol Chem 2003; 278: 359319.
  • 43
    Nagasawa T, Inada Y, Nakano S, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 2006; 536: 18291.
  • 44
    Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation 2007; 115: 51833.
  • 45
    Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S, Muller M. Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology 2007; 148: 275363.
  • 46
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109: 112531.
  • 47
    Foretz M, Guichard C, Ferre P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A 1999; 96: 1273742.
  • 48
    Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 2000; 350: 38993.
  • 49
    Botolin D, Wang Y, Christian B, Jump DB. Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways. J Lipid Res 2006; 47: 18192.
  • 50
    Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 1997; 99: 84654.
  • 51
    Yahagi N, Shimano H, Hasty AH, et al. A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids. J Biol Chem 1999; 274: 358404.
  • 52
    Yoshikawa T, Shimano H, Yahagi N, et al. Polyunsaturated fatty acids suppress sterol regulatory element-binding protein 1c promoter activity by inhibition of liver X receptor (LXR) binding to LXR response elements. J Biol Chem 2002; 277: 170511.
  • 53
    Xu J, Teran-Garcia M, Park JH, Nakamura MT, Clarke SD. Polyunsaturated fatty acids suppress hepatic sterol regulatory element-binding protein-1 expression by accelerating transcript decay. J Biol Chem 2001; 276: 98007.
  • 54
    Xu J, Nakamura MT, Cho HP, Clarke SD. Sterol regulatory element binding protein-1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem 1999; 274: 2357783.
  • 55
    Worgall TS, Sturley SL, Seo T, Osborne TF, Deckelbaum RJ. Polyunsaturated fatty acids decrease expression of promoters with sterol regulatory elements by decreasing levels of mature sterol regulatory element-binding protein. J Biol Chem 1998; 273: 2553740.
  • 56
    Kim HJ, Takahashi M, Ezaki O. Fish oil feeding decreases mature sterol regulatory element-binding protein 1 (SREBP-1) by down-regulation of SREBP-1c mRNA in mouse liver. A possible mechanism for down-regulation of lipogenic enzyme mRNAs. J Biol Chem 1999; 274: 258928.
  • 57
    Delarue J, Couet C, Cohen R, Brechot JF, Antoine JM, Lamisse F. Effects of fish oil on metabolic responses to oral fructose and glucose loads in healthy humans. Am J Physiol 1996; 270: E35362.
  • 58
    Holness MJ, Greenwood GK, Smith ND, Sugden MC. Diabetogenic impact of long-chain omega-3 fatty acids on pancreatic beta-cell function and the regulation of endogenous glucose production. Endocrinology 2003; 144: 395868.
  • 59
    Sampath H, Ntambi JM. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 2005; 25: 31740.
  • 60
    Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 2000; 16: 45981.
  • 61
    Pawar A, Botolin D, Mangelsdorf DJ, Jump DB. The role of liver X receptor-alpha in the fatty acid regulation of hepatic gene expression. J Biol Chem 2003; 278: 4073643.
  • 62
    Roth U, Jungermann K, Kietzmann T. Activation of glucokinase gene expression by hepatic nuclear factor 4alpha in primary hepatocytes. Biochem J 2002; 365: 2238.
  • 63
    Watanabe M, Houten SM, Wang L, et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113: 140818.
  • 64
    Davidson MH. Mechanisms for the hypotriglyceridemic effect of marine omega-3 fatty acids.[see comment]. Am J Cardiol 2006; 98(4A): 2733.
  • 65
    Dentin R, Benhamed F, Pegorier JP, et al. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J Clin Invest 2005; 115: 284354.
  • 66
    Xu J, Christian B, Jump DB. Regulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-alpha agonist. J Biol Chem 2006; 281: 1835162.
  • 67
    Dentin R, Benhamed F, Hainault I, et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 2006; 55: 215970.
  • 68
    Ren B, Thelen AP, Peters JM, Gonzalez FJ, Jump DB. Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha. J Biol Chem 1997; 272: 2682732.
  • 69
    Foretz M, Foufelle F, Ferre P. Polyunsaturated fatty acids inhibit fatty acid synthase and spot-14-protein gene expression in cultured rat hepatocytes by a peroxidative mechanism. Biochem J 1999; 341: 3716.
  • 70
    Valentine RC, Valentine DL. Omega-3 fatty acids in cellular membranes: a unified concept. Prog Lipid Res 2004; 43: 383402.
  • 71
    Clamp AG, Ladha S, Clark DC, Grimble RF, Lund EK. The influence of dietary lipids on the composition and membrane fluidity of rat hepatocyte plasma membrane. Lipids 1997; 32: 17984.
  • 72
    Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med 1993; 328: 23844.
  • 73
    Lo CJ, Chiu KC, Fu M, Chu A, Helton S. Fish oil modulates macrophage P44/P42 mitogen-activated protein kinase activity induced by lipopolysaccharide. JPEN J Parenter Enteral Nutr 2000; 24: 15963.
  • 74
    Guo W, Xie W, Lei T, Hamilton JA. Eicosapentaenoic acid, but not oleic acid, stimulates beta-oxidation in adipocytes. Lipids 2005; 40: 81521.
  • 75
    Larter CZ, Yeh MM. Animal models of NASH: getting both pathology and metabolic context right. J Gastroenterol Hepatol 2008; 23: 163548.
  • 76
    Ishii H, Horie Y, Ohshima S, et al. Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice. J Hepatol 2009; 50: 56271.
  • 77
    Itoh M, Suganami T, Satoh N, et al. Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects. Arterioscler Thromb Vasc Biol 2007; 27: 191825.
  • 78
    Lombardo YB, Hein G, Chicco A. Metabolic syndrome: effects of n-3 PUFAs on a model of dyslipidemia, insulin resistance and adiposity. Lipids 2007; 42: 42737.
  • 79
    Alwayn IP, Gura K, Nose V, et al. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res 2005; 57: 44552.
  • 80
    Alwayn IP, Andersson C, Zauscher B, Gura K, Nose V, Puder M. Omega-3 fatty acids improve hepatic steatosis in a murine model: potential implications for the marginal steatotic liver donor. Transplantation 2005; 79: 6068.
  • 81
    Kajikawa S, Harada T, Kawashima A, Imada K, Mizuguchi K. Highly purified eicosapentaenoic acid prevents the progression of hepatic steatosis by repressing monounsaturated fatty acid synthesis in high-fat/high-sucrose diet-fed mice. Prostaglandins Leukot Essent Fatty Acids 2009; 80: 22938.
  • 82
    Gonzalez-Periz A, Horrillo R, Ferre N, et al. Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins. FASEB J 2009; 23: 194657.
  • 83
    Sekiya M, Yahagi N, Matsuzaka T, et al. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. Hepatology 2003; 38: 152939.
  • 84
    Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol 2006; 169: 84660.
  • 85
    Kim HJ, Lee KT, Park YB, Jeon SM, Choi MS. Dietary docosahexaenoic acid-rich diacylglycerols ameliorate hepatic steatosis and alter hepatic gene expressions in C57BL/6J-Lep(ob/ob) mice. Mol Nutr Food Res 2008; 52: 96573.
  • 86
    Larter CZ, Yeh MM, Cheng J, et al. Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation. J Gastroenterol Hepatol 2008; 23: 26775.
  • 87
    Levy JR, Clore JN, Stevens W. Dietary n-3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats. Hepatology 2004; 39: 60816.
  • 88
    Oliveira CP, Coelho AM, Barbeiro HV, et al. Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease. Braz J Med Biol Res 2006; 39: 18994.
  • 89
    Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 2000; 275: 367037.
  • 90
    Broughton KS, Wade JW. Total fat and (n-3):(n-6) fat ratios influence eicosanoid production in mice. J Nutr 2002; 132: 8894.
  • 91
    Babcock T, Helton WS, Espat NJ. Eicosapentaenoic acid (EPA): an antiinflammatory omega-3 fat with potential clinical applications. Nutrition 2000; 16: 11168.
  • 92
    Yaqoob P, Calder P. Effects of dietary lipid manipulation upon inflammatory mediator production by murine macrophages. Cell Immunol 1995; 163: 1208.
  • 93
    Flachs P, Mohamed-Ali V, Horakova O, et al. Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. Diabetologia 2006; 49: 3947.
  • 94
    Capanni M, Calella F, Biagini MR, et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23: 114351.
  • 95
    Spadaro L, Magliocco O, Spampinato D, et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 2008; 40: 1949.
  • 96
    Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42: 4138.
  • 97
    Sumida Y, Nakashima T, Yoh T, et al. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease. J Hepatol 2003; 38: 328.
  • 98
    Vega GL, Chandalia M, Szczepaniak LS, Grundy SM. Effects of N-3 fatty acids on hepatic triglyceride content in humans. J Invest Med 2008; 56: 7805.
  • 99
    Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40: 138795.
  • 100
    Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2007; 25: 8839.
  • 101
    Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 2003; 38: 4207.
  • 102
    Huang MA, Greenson JK, Chao C, et al. One-year intense nutritional counseling results in histological improvement in patients with non-alcoholic steatohepatitis: a pilot study. Am J Gastroenterol 2005; 100: 107281.
    Direct Link:
  • 103
    Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 2004; 53: 4139.
  • 104
    Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010; 51: 1219.
  • 105
    Harrison SA, Ramrakhiani S, Brunt EM, Anbari MA, Cortese C, Bacon BR. Orlistat in the treatment of NASH: a case series. Am J Gastroenterol 2003; 98: 92630.
    Direct Link:
  • 106
    Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009; 49: 806.
  • 107
    Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol 2003; 12: 18992.
  • 108
    Banasch M, Goetze O, Schmidt WE, Meier JJ. Rimonabant as a novel therapeutic option for nonalcoholic steatohepatitis. Liver Int 2007; 27: 11525.
  • 109
    Dixon JB, Bhathal PS, Hughes NR, O’Brien PE. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 2004; 39: 164754.
  • 110
    Liu X, Lazenby AJ, Clements RH, Jhala N, Abrams GA. Resolution of nonalcoholic steatohepatits after gastric bypass surgery. Obesity Surg 2007; 17: 48692.
  • 111
    Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008; 6: 1396402.
  • 112
    Furuya CK Jr, De Oliveira CP, De Mello ES, et al. Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years. J Gastroenterol Hepatol 2007; 22: 5104.
  • 113
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001; 358: 8934.
  • 114
    Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2005; 21: 8719.
  • 115
    Nobili V, Manco M, Ciampalini P, et al. Metformin use in children with nonalcoholic fatty liver disease: an open-label, 24-month, observational pilot study. Clin Ther 2008; 30: 116876.
  • 116
    Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005; 100: 108290.
    Direct Link:
  • 117
    Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther 2008; 29: 17282.
  • 118
    Caldwell SH, Hespenheide EE, Redick JA, Iezzoni JC, Battle EH, Sheppard BL. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96: 51925.
    Direct Link:
  • 119
    Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003; 38: 100817.
  • 120
    Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004; 39: 18896.
  • 121
    Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 2008; 135: 10010.
  • 122
    Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297307.
  • 123
    Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A. Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 2001; 15: 166772.
  • 124
    Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98: 248590.
    Direct Link:
  • 125
    Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003; 38: 4139.
  • 126
    Merat S, Malekzadeh R, Sohrabi MR, et al. Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatol 2003; 38: 4148.
  • 127
    Satapathy SK, Garg S, Chauhan R, et al. Beneficial effects of tumor necrosis factor-alpha inhibition by pentoxifylline on clinical, biochemical, and metabolic parameters of patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 194652.
    Direct Link:
  • 128
    Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 23658.
    Direct Link:
  • 129
    Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004; 39: 7708.
  • 130
    Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004; 40: 12225.
  • 131
    Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol 2009; 15: 94254.
  • 132
    Abdelmalek MF, Angulo P, Jorgensen RA, Sylvestre PB, Lindor KD. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001; 96: 27117.
    Direct Link:
  • 133
    Pamuk GE, Sonsuz A. N-acetylcysteine in the treatment of non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2003; 18: 12201.
  • 134
    Chande N, Laidlaw M, Adams P, Marotta P. Yo Jyo Hen Shi Ko (YHK) improves transaminases in nonalcoholic steatohepatitis (NASH): a randomized pilot study. Dig Dis Sci 2006; 51: 11839.