Role of diet and nutritional management in non-alcoholic fatty liver disease

Authors

  • Jian-Gao Fan,

    Corresponding author
    1. Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Children's Digestion and Nutrition, Shanghai, China
    • Correspondence

      Professor Jian-Gao Fan, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Email: fanjiangao@gmail.com

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  • Hai-Xia Cao

    1. Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Children's Digestion and Nutrition, Shanghai, China
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  • Conflict of interest: None.
  • Invited review article for the 3rd APTC supplement.

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis, which causes an increased risk of cirrhosis, type 2 diabetes, and cardiovascular complications. With the worldwide growing incidence of obesity, sedentary lifestyle, and unhealthy dietary pattern, NAFLD has currently been recognized as a major health burden. Dietary patterns and nutrients are the important contributors to the development, progression, and treatment of NAFLD and associated metabolic comorbidities. Generally, hypercaloric diet, especially rich in trans/saturated fat and cholesterol, and fructose-sweetened beverages seem to increase visceral adiposity and stimulate hepatic lipid accumulation and progression into non-alcoholic steatohepatitis, whereas reducing caloric intake, increasing soy protein and whey consumption, and supplement of monounsaturated fatty acids, omega-3 fatty acids, and probiotics have preventive and therapeutic effects. In addition, choline, fiber, coffee, green tea, and light alcohol drinking might be protective factors for NAFLD. Based on available data, at least 3–5% of weight loss, achieved by hypocaloric diet alone or in conjunction with exercise and behavioral modification, generally reduces hepatic steatosis, and up to 10% weight loss may be needed to improve hepatic necroinflammation. A sustained adherence to diet rather than the actual diet type is a major predictor of successful weight loss. Moreover, a healthy diet has benefits beyond weight reduction on NAFLD patients whether obese or of normal weight. Therefore, nutrition serves as a major route of prevention and treatment of NAFLD, and patients with NAFLD should have an individualized diet recommendation.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is an acquired metabolic stress-related liver disease sharing histological similarities to alcoholic liver disease in the absence of substantial alcohol consumption.[1, 2] The spectrum of NAFLD is from simple steatosis to non-alcoholic steatohepatitis (NASH), and eventually cirrhosis and hepatocellular carcinoma.[1, 2] NAFLD is strongly associated with obesity, dyslipidemia, hypertension, type 2 diabetes mellitus (T2DM), and metabolic syndrome.[1-3] With the rising incidence of obesity and metabolic syndrome in adults and children worldwide, NAFLD is developing into a new and major health problem.[1-3] Currently, NAFLD/NASH is the most common cause of liver disease worldwide and the third most common indication for liver transplantation in North America.[1] The management of patients with NAFLD consists of treating steatohepatitis and the associated metabolic comorbidities.[1, 2] However, patient with simple steatosis is only needed to treat the associated conditions to prevent hepatic and metabolic complications.[1, 2]

Based on available data, most patients with NAFLD have excessive body weight or recently, weight gain; obesity is a common and well-documented risk factor for metabolic syndrome and NAFLD.[1-3] Although promising pharmacological agents and bariatric surgery are emerging, gradually and maintaining weight loss by lifestyle intervention is safe and the most effective treatment for NAFLD and metabolic disorders.[1, 2, 4-9] On one hand, diet alone or in conjunction with increased physical activity and behavior modification is the important measure for successful weight loss. On the other hand, unhealthy dietary patterns and unbalanced nutrients are not only strongly associated with the development and progression of NAFLD but is also risk factors for obesity and metabolic syndrome. Moreover, a healthy diet has benefits beyond weight reduction for all NAFLD patients with and without obesity.[4-9] Therefore, dietary nutritional management should be a component of any treatment plan for NAFLD. This review discusses the role of dietary modification in the management of patients with NAFLD.

Effects of weight loss diet on NAFLD

Obesity is associated with such health problems as an increased risk of NAFLD/NASH, T2DM, coronary heart disease, cancer (e.g. liver, kidney, breast, endometrial, prostate, colon), gallstones, and disability.[10] These comorbid medical conditions are associated with higher use of health care services and costs among obese patients, and weight loss in these individuals is associated with a lower morbidity and mortality.[10] Therefore, the US Preventive Services Task Force recommends screening all adults for obesity. Clinicians should offer or refer patients with a body mass index ≥ 30 kg/m2 to intensive, multicomponent behavioral interventions.[10] Although there are many therapeutic weight loss techniques used in obese patients with NAFLD (Table 1), the least intrusive weight loss methods and those most often recommended are adjustments to eating patterns and increased physical activity.[1, 10, 11]

Table 1. Therapeutic weight loss techniques in non-alcoholic fatty liver disease (NAFLD)
CategoriesDescription or recommendation
  1. NASH, non-alcoholic steatohepatitis; USPSTF, US Preventive Services Task Force.
Dietary modificationAt least 3–5% of weight loss achieved by hypocaloric diet with or without exercise, generally reduces hepatic steatosis, and 10% weight loss may be needed to improve necroinflammation.
Increased physical activity

A regular exercise program with 200 min/week of moderate-intensity.

Exercise alone in adults with NAFLD may only reduce hepatic steatosis.

Behavioral interventions

Included self-monitoring, setting weight loss goals, addressing barriers to change, and strategizing about maintaining long-term changes in lifestyle.

Participants received behavioral interventions usually lost 4% of baseline weight at 12–18 months.

Pharmacological agents

Aim to decrease appetite, block fat absorption, or reduce stomach volume, only be used under the strict supervision of a specialist.

Diet drug is not recommended for the treatment of obesity by the USPSTF.

Bariatric surgeryForegut bariatric surgery is not contraindicated in otherwise eligible obese individuals with NAFLD/NASH; it is premature to consider it as an established option to specifically treat NASH.
Dietary supplementsAlthough a wide array of dietary supplements available to the public, very few are effective in long term and are not considered a healthy option for weight loss.

It is well known that the liver is primarily a metabolic organ that regulates a complex array of physiological and biochemical processes, including energy and lipid metabolism. Excess energy and unmatched energy expenditure can result in the accumulation of fat in the visceral adiposity and liver. Although patients with NAFLD do not always intake higher energy, they have excess consumption of saturated fat/energy and higher simple carbohydrate intake when compared with healthy controls. The development and progression of NAFLD is closely associated with the unhealthy dietary pattern; many dietary factors are associated with NAFLD (Table 2).[1, 3-7, 12-28] Weight management, dietary macronutrient composition, physical activity, and behavior therapy all play a critical role in weight loss.[1, 2, 10, 11] Recently, Thoma and colleagues applied a systematic approach to evaluating lifestyle modifications in adult populations with NAFLD studied to date.[11] They identified 23 studies for inclusion; seven had control groups, but only six were randomized. Eleven groups received diet-only interventions, two exercise-only, and 19 diet and physical activity/exercise. Studies consistently showed reductions in liver fat and/or serum aminotransferase concentration, with the strongest correlation being with weight reduction. Of the five studies reporting changes in hepatic histopathology, all showed a trend toward reduction in inflammation; in two, this was statistically significant. Changes in liver fibrosis were less consistent, with only one study showing a significant reduction. The majority of studies also reported improvements in glucose control/insulin sensitivity following intervention. In addition, lifestyle modifications leading to weight loss diet and/or increased physical activity consistently improved glucose control/insulin sensitivity. Another systematic review and meta-analysis of randomized trials by Musso et al. suggests that lifestyle-induced weight loss is safe and improved cardiometabolic risk profile; a weight loss ≥ 7% improved hepatic histological disease activity but was achieved by < 50% patients.[29] A weight loss of 5% is considered clinically important by the US Food and Drug Administration.[10] The results of several original articles published in the past 2 years also show that diet-induced weight loss reduces liver enzymes and hepatic steatosis (Table 3).[30-32] Therefore, the US Practice Guideline for the Diagnosis and Management of NAFLD recommend that weight loss achieved either by hypocaloric diet alone or in conjunction with increased physical activity generally reduces hepatic steatosis. At least 3–5% of weight loss appears necessary to improve steatosis, but a greater weight loss (∼ 10%) may be needed to improve necroinflammation.[1]

Table 2. Dietary nutrient associated with metabolic disorders and non-alcoholic fatty liver disease (NAFLD)
Risk factorProtective factorUncertain factor
  1. GI, glycemic index; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids.
High fat intakeLight alcohol drinkingTotal caloric intake
More saturated fatty acids (Lard, butter, coconut oil, palm oil)Coffee drinkingTotal protein intake
More trans-fatty acids (Fast foods, baked goods, deep fried foods, margarine)Green teaExcessive n-6 fatty acids
Lower intake of PUFAMUFA (Olive oil, nuts, avocados, peanut butter, peanut oil)Dietary antioxidants (vitamin C or E, ginger, genistein)
High cholesterol intaken-3 fatty acids (fish oil, walnuts, salmon, shellfish)Betaine
High carbohydrates intakeLow-GI foods (oats, soya and linseed, whole grain)Probiotic-rich foods (yogurt, kefir)
High simple carbohydrates intakeSoy protein and whey 
High fructose and sucrose intake (soft drink, candy)Dietary fiber (whole grains, fruits, vegetables) 
Decreased fruit intake  
Decreased choline intake (associated with increased fibrosis in postmenopausal women with NAFLD)  
Table 3. The effects of diet and dietary nutrients on NAFLD in recently clinical trials
StudyTypeInterventionResults
  1. ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; CRP, C-reactive protein; GGT, gammaglutamine transferase; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment-insulin resistance; LDL, low-density lipoprotein; MRS, proton magnetic resonance spectroscopy; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; RCT, randomized, controlled trial; TNF, tumor necrosis factor.
Sevastianova et al., 2012[32]

Observational

n = 16 (obese adults)

Hypercaloric diet rich in simple carbohydrates 3 weeks and then hypocaloric diet 6 months.Hypercaloric diet increased weight by 2% and liver fat (measured by MRS) by 27%. Hypocaloric diet loss weight by 4% and liver fat by 25%.
Rodríguez-Hernández et al., 2011[30]

non-controlled clinical intervention

n = 59 (obese women)

Low carbohydrate diet versus low-fat diet during 6 months.No significant differences in the anthropometric and biochemical characteristics in both groups.
Grønbæk and colleague, 2012[31]

Observational study

n = 71 (obese children, partly with NAFLD)

Exercised moderately for 1 h/day and restricted energy intake for 10 weeks at the camp.Average weight loss of 7 kg during the camp, with reduction of ultrasonographic steatosis, elevated transaminases, and reduced insulin sensitivity. Liver fat improvement was sustained, and 24% maintained the body weight at 12 months.
Bjermo et al., 2012[21]

RCT

n = 61 (NAFLD)

Isocaloric diet high in vegetable n-6 PUFA versus SFA mainly from butter for 10 weeks.Reduction in serum insulin, total/HDL-cholesterol ratio, LDL cholesterol, triglycerides, and liver fat (assessed by MRS).
Nobili et al., 2011[35]

RCT

n = 60 (children with biopsy-proven NAFLD)

Docosahexaenoic acid (DHA) supplementation (250 and 500 mg/day) versus placebo for 6 months.Insulin sensitivity increased, serum triglycerides decreased, the odds of more severe versus less severe liver steatosis lower in both DHA groups but no difference between the DHA groups. No effect on ALT and BMI.
Bortolotti et al., 2011[23]

Observational study

n = 11 (obese women without diabetes)

60 g/day whey protein supplement for 4 weeks, while otherwise nourished on spontaneous diet.Decreased liver fat (assessed by MRS), fasting triglycerides, and total cholesterol; and slightly increased fat-free mass. Visceral fat, total liver volume, glucose tolerance, creatinine clearance, and insulin sensitivity not changed.
Lavine et al., 2011[39]

RCT

n = 116 (8–17 years, biopsy-proven NAFLD)

800 IU vitamin E daily versus placebo for 96 weeks.Sustained reduction in ALT and improvements in histological features similar to the placebo group.
Aller et al., 2011[41]

RCT

n = 28 (biopsy-proven NAFLD)

Mixture containing 500 million of Lactobacillus bulgaricus and Streptococcus thermophilus per day versus placebo for 3 months.Decreased serum ALT, AST, and GGT levels. Anthropometric parameters and cardiovascular risk factors remained unchanged.
Malaguarnera et al., 2012[42]

RCT

n = 66 (biopsy-proven NASH)

Bifidobacterium longum with Fos and lifestyle modification versus lifestyle modification alone for 24 weeks.Reduction in serum endotoxin, TNF-α, CRP, AST levels, HOMA-IR, and hepatic steatosis and the NASH activity index.

Diets to promote weight loss or to maintain a stable body weight are generally divided into four categories: low fat, low carbohydrate, low calorie, and very low calorie (Table 4).[8-10] A meta-analysis of six randomized, controlled trials (RCTs) found no difference between the main diet types (low calorie, low carbohydrate, and low fat), with a 2–4 kg (approximately 4% of baseline weight) weight loss at 12–18 months in all studies.[9] The very low-calorie diets are not recommended for general use, as they are associated with adverse side-effects and only prescribed on a case-to-case basis for rapid weight loss (about 1.5–2.5 kg/week) in some severe obese patients.[8, 9] However, large fluctuations in weight can exacerbate liver injury and result in liver failure in patients with NASH.[1, 2, 4-6] It is particularly important to achieve slow and sustained weight loss during treatment and follow-up. Moreover, long-term studies of dieting indicate that the majority of individuals who dieted regain virtually all of the weight that was lost after dieting, regardless of whether they maintain their diet or exercise program.[8-10] Therefore, the maintenance of weight loss is still one of the biggest challenges of dietary interventions in patients with NAFLD.

Table 4. Classification of weight loss diet in patients with non-alcoholic fatty liver disease
CategoriesDescription
Low-fat dietsThe reduction of the percentage of fat in diet (25% fat), without intentional restriction of caloric intake.
Low-carbohydrate dietsThe reduction of the percentage of carbohydrates in diet, that is, Atkins and Protein Power, relatively high in protein and fats, sometimes lead to ketogenic.
Low-calorie dietsProvide about 1000–1200 calories a day for women and 1500 to 1800 calories for men.
Very low-calorie diets

Provide 200–800 calories per day, maintaining protein intake but limiting calories from both fat and carbohydrates.

Must be undertaken with medical supervision to prevent adverse side-effects, such as loss of lean muscle mass, increased risks of gout, gallbladder stone, and electrolyte imbalances.

Influence of macronutrients on NAFLD

Aside from the possibility of achieving weight loss through caloric restriction (either low in carbohydrates or low in fats) as a treatment for NAFLD, many dietary factors (especially macronutrients) can directly influence the development of NAFLD (Table 2).[3-7, 12-27] Manipulation of dietary composition might affect the outcomes of NAFLD and associated metabolic disorders independent of weight loss.[4-6]

Carbohydrates

The dietary carbohydrates are often divided into complex carbohydrate (refer to any sort of digestible saccharide present in a whole food, where fiber, vitamins, and minerals are also found), or simple carbohydrates such as monosaccharides and disaccharides (refer to sugar, provide calories but few other nutrients, and raise blood glucose rapidly especially if processed). Dietary carbohydrate especially sugars contribute to increased circulating insulin and triglyceride concentrations and lead to increased hepatic de novo lipogenesis and decreased hepatic insulin sensitivity because of the lipogenic potential of fructose during liver metabolism.[12-16] In addition, recent genome-wide studies have identified several polymorphisms that contribute to increased liver fat accumulation, with some of these genes relating to dietary carbohydrate and sugar consumption.[7, 33] Dietary fructose consumption primarily in the form of soft drinks worldwide has increased in parallel with the increase in obesity, diabetes, and NAFLD, and some studies have suggested a direct association.[1-6] The role of fructose and sucrose in NAFLD and metabolic disorders has been thoroughly reviewed elsewhere.

Low-carbohydrate diets are increasingly employed for treatment of obesity and NAFLD; they have been shown to promote weight loss, decrease intrahepatic triglyceride content, and improve metabolic parameters of patients with obesity.[4-6, 9, 34] However, the relationship between long-term maintenance on low-carbohydrate diets and systemic insulin resistance in humans remains to be elucidated. In addition, low glycemic index (GI ≤ 55) foods such as oats have been shown to increase appetite, reduce calories intake, and decrease plasma glucose and total cholesterol levels.[4-6, 9, 34] Therefore, GI may be an important factor to consider when giving dietary recommendations to patients with NAFLD. However, there are no studies in human beings examining the effects of GI specifically in these patients to date.

Fat

Increased fat intake and Western diets have been linked to insulin resistance, impaired postprandial lipid metabolism, and the development or progression of NAFLD.[4-6] Patients with NAFLD often consume more saturated fatty acid (SFA) and less polyunsaturated fatty acid (PUFA), especially n-3 PUFA.[4-6, 18-21] SFA has adverse effects on lipid and glucose homeostasis, which in turn worsen the progression of metabolic syndrome and possibly NAFLD.[4-6] Moreover, dietary SFA and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH in mice.[17] Dietary SFA and cholesterol are thus major targets for reducing plasma total and low-density lipoprotein cholesterol as a strategy to decrease cardiovascular disease risk in patients with NAFLD.[4-6] However, whereas diets containing 8–10% SFA are likely to be beneficial, extreme reductions in SFA (< 6%) may have deleterious effects on plasma lipid levels.[4-6]

Supplementation of monounsaturated fatty acid (MUFA) and/or PUFA is currently investigated as a potential treatment against NAFLD.[4-6] An increase in MUFA intake, especially as a replacement for SFA, may offset the pro-inflammatory effects of SFA, may induce a more favorable plasma lipid profile, may reduce insulin resistance, and may thus reduce the risk of metabolic syndrome and NAFLD/NASH.[4-6] PUFAs of the n-3 and n-6 series are essential fatty acids that must be provided by the diet.[4-6, 19-21] Fish oils rich in eicosapentaenoic and docosahexaenoic acids are the most biologically active n-3 PUFAs and exhibit protective effects.[4-6] In a recent systemic review and meta-analysis, it has been concluded that omega-3 PUFA supplementation may decrease liver fat but could not reduce serum aminotransferases levels.[19] At present, well-designed RCTs that quantify the magnitude of effect of omega-3 PUFA supplementation on liver fat are needed.[35] Therefore, it is premature to recommend omega-3 fatty acids for the specific treatment of NAFLD or NASH, but they may be considered as the first-line agents to treat hypertriglyceridemia in patients with NAFLD.[1] In addition, compared with SFA intake, n-6 PUFAs may reduce liver fat and modestly improve metabolic status as well.[21]

Protein

Until now, only a few human studies addressed protein intake and metabolic syndrome or NAFLD.[4-6] High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients and blunt the effects of a high-fat diet on intrahepatocellular lipids.[4-6, 22-24] The short-term consumption of soy protein as part of a low-energy diet may provide an additional benefit for weight reduction in subjects with obesity and decrease serum alanine transaminase levels and hepatic steatosis in patients with chronic hepatitis C.[22, 36] However, protein is well represented in the Western diet; thus, deficiency is unlikely. Excess protein intake can have untoward effects on renal function in susceptible individuals.[24] Currently, the contribution of dietary protein especially the type of dietary protein to the process of obesity and its metabolic consequences are less well understood. Therefore, conclusive evidence is lacking to make a definitive statement regarding the effect of dietary protein on NAFLD.

Influence of micronutrients and food supplements on NAFLD

Recent literatures suggest that some micronutrients and food supplements are associated with the development of or treatment for NAFLD.[25-28, 37-42] Choline is an essential nutrient, humans eating low-choline diets develop fatty liver and liver damage. However, this dietary requirement for choline is modulated by estrogen and by single nucleotide polymorphisms in specific genes of choline and folate metabolism. Decreased choline intake is significantly associated with increased fibrosis only in postmenopausal women with NAFLD.[25] Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in NAFLD.[1] Green tea is rich in polyphenolic catechins that have anti-oxidant, hypolipidemic, thermogenic, and anti-inflammatory activities that may mitigate the occurrence and progression of NAFLD.[26] Coffee caffeine consumption is independently associated with a lower risk for NAFLD and associated with a significant reduction in risk of fibrosis among NASH patients. These data suggest a potential protective effect of tea and coffee on NAFLD.[27, 28] Recently, Dunn et al. reported that modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis and fibrosis in a large well-characterized population with biopsy-proven NAFLD.[38] These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD. Vitamin E is an anti-oxidant as well and has been investigated to treat NASH.[1, 39] According to the US Practice Guideline for the Diagnosis and Management of NAFLD, vitamin E (a-tocopherol) administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH, and therefore, it should be considered as a first-line pharmacotherapy for this patient population.[1] Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.[1] However, Klein et al. reported that dietary supplementation with vitamin E (400 IU/day of all rac-α-tocopheryl acetate) significantly increased the risk of prostate cancer among healthy men in 7–12 years follow-up of the Selenium and Vitamin E Cancer Prevention Trial.[40]

Recent evidence has linked obesity and metabolic syndrome with gut dysbiota. Modifications of the gut microbiota may play a role in the development and progression of NAFLD.[41] Probiotics are live microbial food supplements or components of bacteria, and may have beneficial effects on human health. Emerging data suggest that probiotics treatment improve liver chemistry tests and reduce liver fat in NASH patients.[42, 43] Future research should focus on placebo-controlled, clinical trials using histological end-points to address the effects of prebiotics on NAFLD and NASH.

Conclusion

There is growing evidence that diet and nutrients can affect the pathophysiology of NAFLD. The influence of the dietary nutrients is important and can help to treat NAFLD and associated metabolic comorbidities. In general, hypercaloric diet, high dietary SFA and cholesterol, and soft drinks seem to increase stimulate hepatic lipid accumulation and progression into NASH, whereas reducing total caloric intake, increasing soy protein and whey consumption, and the supplements of MUFA, omega-3 fatty acids, and probiotics have preventive and therapeutic effects. Gradually and maintaining weight loss by lifestyle intervention is the most effective treatment for NAFLD, and a sustained adherence to caloric restriction (either low in carbohydrates or low in fats) is a major predictor of weight loss. In addition, a healthy dietary pattern and some nutrients have benefits beyond weight reduction on NAFLD patients. Therefore, diet and nutrient management should be a component of any treatment plan for patients with NAFLD, these patients should follow a well-balanced diet (Table 5). However, research focusing on specific dietary components predisposing to NAFLD or used for treatment of NAFLD has shown conflicting results to date. Currently, well-designed dietary intervention trials are needed to create definitive evidence-based dietary guidelines for NAFLD.

Table 5. Recommend low-calorie diet modified by the NHLBI guidelines for weight loss
NutrientRecommended intake
  1. NHLBI, National Heart, Lung and Blood Institute.
Total energy intakeApproximately 500–1000 kcal/day reduction from usual state
Total fat intake< 35% of total calories
Saturated fatty acids8–10% (< 7% while hypercholesteremia) of total calories; avoid transfatty acids
Monounsaturated fatty acidsUp to 15% of total calories
Polyunsaturated fatty acidsUp to 10% of total calories; increase omega-3 fatty acids
Cholesterol intake< 300 mg/day (< 200 mg/day while hypercholesteremia)
Protein intakeApproximately 15% of total calories; lean animal- or plant-based protein
Carbohydrate intake≥ 55% of total calories, 50% or more of whole grains, avoid high-fructose soft drinking
Fiber20–30 g/day (with an upper limit of 35 g/day)
Sodium chlorideNo more than 100 mmol daily (approximately 6 g/day)
Calcium1000–1500 mg/day

Acknowledgments

Funding was provided by the State Key Development Program for Basic Research of China (2012CB517500), the National Natural Science Foundation of China (81070322 & 81270491), the Program of the Shanghai Committee of Science and Technology (09140903500 & 10411956300), the 100 Talents Program of the Shanghai Board of Health (XBR2011007).

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