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High consumption of dietary fructose is an important contributory factor in the development of hepatic steatosis in insulin or leptin resistance. We investigated the effects of curcumin on fructose-induced hypertriglyceridemia and liver steatosis and explored its preventive mechanisms in rats. Curcumin reduced serum insulin and leptin levels in fructose-fed rats. This compound could increase phosphorylation of insulin receptor and insulin receptor substrate 1 to enhance Akt and extracellular signal-regulated kinase1/2 (ERK1/2) activation in the liver of fructose-fed rats. Moreover, curcumin increased phosphorylation of hepatic janus-activated kinase-signal transducer 2 and subsequently also stimulated Akt and ERK1/2 activation in this model. Suppression of curcumin on leptin signaling overstimulation in tyrosine1138 phosphorylation of the long form of leptin receptor and signal transducer and activator of transcription 3 resulted in down-regulation of suppressor of cytokine signaling 3 in the liver of fructose-fed rats. Thus, improvement of insulin and leptin signaling transduction and subsequently elevation of peroxisome proliferator-activated receptor α expression by curcumin led to reduction of very-low-density lipoprotein overproduction and triglyceride hypersynthesis. Furthermore, overexpression and hyperactivity of hepatic protein tyrosine phosphatase 1B (PTP1B) associated with defective insulin and leptin signaling were observed in fructose-fed rats. Additionally, curcumin was found to significantly reduce hepatic PTP1B expression and activity in this model. Conclusion: Our data indicate that the mechanisms by which curcumin protects against fructose-induced hypertriglyceridemia and hepatic steatosis are its inhibition on PTP1B and subsequently improvement of insulin and leptin sensitivity in the liver of rats. This PTP1B inhibitory property may be a promising therapeutic strategy for curcumin to treat fructose-induced hepatic steatosis driven by hepatic insulin and leptin resistance. (HEPATOLOGY 2010.)
The prevalence of nonalcoholic steatohepatitis (NASH) is rapidly increasing with the worldwide changes of dietary pattern. High fructose consumption is a risk factor for NASH.1, 2 The pathogenesis of fructose-induced hypertriglyceridemia and hepatic steatosis is associated with insulin and/or leptin resistance.3-6 Fructose decreases tyrosine (Tyr) phosphorylation of insulin-induced insulin receptor substrate 1 (IRS1) and inhibits activation of Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in peripheral tissues of rats.7, 8 Impaired insulin signaling aggravates insulin resistance and suppresses action of insulin on hepatic very-low-density lipoprotein (VLDL) production and triglyceride (TG) secretion, the leading lipid metabolism abnormality in the liver of fructose-fed hamster.3, 4, 7 Moreover, fructose-induced hyperleptinemia is observed in animals and humans.5, 6, 9 The main action of hepatic leptin is to decrease fatty acid synthesis and to increase fatty oxidation by increasing peroxisome proliferator-activated receptor α (PPARα) activity, thus reducing hepatic TG synthesis.10 In fructose-fed rats, overexpression of suppressor of cytokine signaling 3 (SOCS3) evoked by high leptin through signal transducer and activator of transcription 3 (STAT3) blocks hepatic leptin signaling transduction targeting janus-activated kinase-signal transducer 2 (JAK2).6 ERK1/2 are members of mitogen-activated protein kinase family, which modules PPARα activity. Impaired leptin signaling transduction induced by fructose decreases hepatic fatty acid oxidation through reduction of ERK1/2 activation and PPARα activity.5, 6 These observations suggest that impairment of insulin or leptin signaling transduction is involved in fructose-induced hypertriglyceridemia and hepatic steatosis.
Protein-tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling.11 Hepatic PTP1B expression is increased in insulin-resistant diabetes and obesity.12 Mice lacking PTP1B show insulin sensitivity with enhanced phosphorylation of hepatic insulin receptor (IR) and IRS1.13 The ability of PTP1B to dephosphorylate JAK2 indicates that PTP1B may be involved in the regulation of leptin signaling pathway.14 PTP1B-deficient mice are protected against diet-induced obesity and hypersensitive to leptin.15 Increased hepatic PTP1B expression is also found in the insulin-resistant state in fructose-fed hamsters.16, 17 These observations indicate that fructose-induced insulin and leptin resistance may be associated with PTP1B abnormality in the liver of animals. However, it is unclear how changes in hepatic insulin and leptin signaling via PTP1B dysregulation can develop lipid metabolism disorder and hepatic steatosis in fructose-fed rats.
Curcumin is an inexpensive dietary supplement with multiple beneficial effects on the pathophysiological processes involved in the development and progression of NASH.18, 19 This compound exhibits protection against experimental and clinic hepatic steatosis by improving inflammation, hyperlipidemia, and insulin and leptin resistance.18-21 However, the mechanisms underlying its protective actions in fructose-induced hepatic steatosis are not completely understood. Inhibition of PTP1B may represent a novel therapeutic approach for the prevention and treatment of hypertriglyceridemia and hepatic steatosis in insulin and leptin resistance. The current study demonstrated that inhibition of curcumin in increased expression and activity of PTP1B was parallel with its improvement in impairment of insulin and leptin signaling transduction in the liver of fructose-fed rats. Therefore, curcumin could prevent hypertriglyceridemia and hepatic steatosis via its amelioration of hepatic insulin and leptin resistance in fructose-fed rats. Pioglitazone, which exhibits inhibitory effect on PTP1B activity in high-fat rats22 and has proved useful for treating patients with NASH,23 was employed as a positive control in this study. Our results provide novel insights into the potential therapeutic mechanisms of curcumin on fructose-induced hepatic steatosis associated with insulin and leptin resistance.
APES, 3-Aminopropyltriethoxysilane; ERK1/2, extracellular signal-regulated kinase 1/2; GTT, glucose tolerance test; IR, insulin receptor; IRS1, insulin receptor substrate 1; ITT, insulin tolerance test; JAK2, janus-activated kinase-signal transducer 2; MCF-7, Michigan Cancer Foundation-7; mRNA, messenger RNA; NASH, nonalcoholic steatohepatitis; ObRL, the long form of leptin receptor; PPARα, peroxisome proliferator-activated receptor α; PTP1B, protein-tyrosine phosphatase 1B; SEM, standard error of the mean; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; TC, total cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor α; Tyr, tyrosine; VLDL, very low-density lipoprotein.
Materials and Methods
Male Sprague-Dawley rats (4 weeks of age, weighing 200-220 g) were used in experiments. Rats were housed with water and food ad libitum at constant humidity and temperature with a light/dark cycle of 12 hours. All procedures on animals followed guidelines established by the Institutional Animal Care Committee at the Nanjing University and the China Council on Animal Care at Nanjing University.
Rats were given 10% (wt/vol) fructose in drinking water and standard rat chow for 8 weeks. Fresh drinking water was replaced every 2 days. At week 4, tail-vein blood samples were obtained at 11:00 AM after 16 hours of fasting. Fructose-fed rats were randomized into five groups (n = 8) to receive water (vehicle), 15, 30, and 60 mg/kg curcumin (97.3%, Jin Yu Jin Co., Ltd. P. R. China), 10 mg/kg pioglitazone (95%, Sigma Chemicals, St. Louis, MO) for an additional 4 weeks, respectively. All drugs were given orally once daily at 2:00 PM to 3:00 PM. In addition, eight animals remained on regular chow for 8 weeks to serve as normal control. Intakes of food and drinking water were recorded daily in metabolic cages, respectively.
Glucose Tolerance Test and Insulin Tolerance Test.
At the end of drug treatment, the glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed, respectively. Rats were weighed and then orally administered with glucose (1.5 g/kg body weight) or intraperitoneally injected with insulin (0.8 U/kg body weight). Tail-vein blood samples were collected at baseline and at indicated time intervals after glucose or insulin treatment, respectively, and centrifuged (3000g) at 4°C for 10 minutes to get serum for glucose assay with glucose oxidase method (Glucose Analyzer; Beckman Instruments, Irvine, CA).
Blood and Liver Sample Collection.
After GTT and ITT, all animals were allowed 3 days to recover wounds. Then they were sacrificed after a 16-hour fasting. Blood samples were collected and serum was used for biochemical assays. Liver tissues were dissected quickly on ice. Parts of them were immediately fixed for histological analysis, and others were stored in liquid nitrogen for biochemical and molecular analysis.
Histological Analysis of Liver.
Rat livers were removed and immediately fixed for 1 day at room temperature in Carnoy fixative (ethanol: chloroform: acetic acid = 6:3:1) and preserved in 70% ethanol. Renal biopsy specimens were dehydrated with a graded series of alcohol and embedded in paraffin. Specimens were cut in 7-μm-thick section on a rotary microtome and mounted on 3-aminopropyltriethoxysilane (APES)-coated glass slides. Each section was deparaffinized in xylene, rehydrated in decreasing concentrations of alcohol in water, and stained with hematoxylin-eosin reagent (Sigma Chemicals Co., St. Louis, MO). The slide was mounted with neutral balsam.
Serum and Liver Tissue Analyses.
Liver lipids were extracted according to the method of Bligh and Dyer,24 in which the chloroform layer was used to determine TG, VLDL, and total cholesterol (TC) levels. Serum and hepatic TG levels and hepatic TC levels were determined using common biochemical kits (JianCheng Bioengineering Institute, Nanjing, China). Serum and hepatic VLDL concentrations, as well as serum insulin, leptin, and tumor necrosis factor (TNF)-α levels, were examined using enzyme-linked immunosorbent assay kits (R&D Systems Inc., Minneapolis, MN), respectively.
PTP1B Activity in Liver.
Liver tissues were homogenized in 10 wt/vol of lysis buffer (50 mM 4-[2-hydroxyethyl]-1-piperazine ethanesulfonic acid, 0.1 mM ethylene glycol tetra-acetic acid, 0.1 mM ethylene diamine tetra-acetic acid, 120 mM NaCl, 0.5% NP-40, 25 μg/mL leupeptin, 25 μg/mL pepstatin, 2 μg/mL aprotinin, 1 mM phenylmethane sulfonyl fluoride, pH 7.5) on ice-bath, and then centrifuged at 14,000g for 15 minutes at 4°C. The supernatants were collected and protein concentrations were determined by Bradford method (Bio-Rad Laboratories, Hercules, CA). PTP1B activity was measured using a PTP1B assay kit (Upstate Biotechnology, Inc, Charlottesville, VA).
RNA Preparation and Analysis.
Gene expression analysis in rat livers was performed by semiquantitative reverse transcription polymerase chain reaction method. Total RNA was extracted from tissues using Trizol reagent (Invitrogen Corp., Carlsbad, CA) following the manufacturer's instructions. For analysis, total RNA (1 μg) was reverse-transcribed using Moloney murine leukemia virus transcriptase (Promega Co., Madison, WI) and a deoxythymidine oligonucleotides [oligo(dT)12-18] primer (Invitrogen Biotechnologies) at 42°C for 1 hour. Primes, annealing temperatures and production lengths set for JAK2, STAT3, SOCS3, PPARα and PTP1B are shown in Table 1. Polymerase chain reaction products were electrophoresed on 1.2% agarose gels, visualized with Bio-Rad ChemiDoc XRS Gel Documentation system, and then quantified using Bio-Rad Quantity One 1-D analysis software.
Table 1. Sequences of Primer Pairs Used for Amplification of mRNA by PCR
Western Blot Analysis.
Liver tissues were homogenized in 10 wt/vol buffer (10 mM Tris-HCl, 1 mM ethylenediaminetetra-acetic acid and 250 mM sucrose, pH 7.4, containing 15 μg/mL aprotinin, 5 μg/mL leupeptin, 0.1 mM phenylmethanesulfonyl fluoride, 1 mM NaF, and 1 mM Na3VO4) and centrifuged at 3000g for 15 minutes at 4°C. The supernatant was again centrifuged at 12,000g for 20 minutes at 4°C. After resolution of liver protein (equal loading for each sample) by 12% sodium dodecyl sulfate polyacrylamide gel electrophoresis, the protein samples were electrophoretically transferred onto polyvinylidene difluoride membranes (Millipore, Shanghai, P. R. China). Nonspecific protein-binding sites were blocked with phosphate-buffered saline containing 0.1% Tween-20 and 5% fat-free milk for 1 hour at room temperature. Antibodies were obtained from Santa Cruz Technologies, except IR, P-IR, IRS1, P-IRS1, JAK2, P-JAK2, STAT3, P-STAT3, SOCS3, Akt, P-Akt, and P-ERK 1/2 were purchased from Cell Signaling (Danvers, MA). Immunoreactive bands were visualized via a phototope-horseradish peroxidase western blot detection system (Cell Signaling Technologies, Beverly, MA) and quantified via densitometry using Molecular Analyst software (Bio-Rad Laboratories, Hercules, CA).
Data were presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using the GraphPad Prism 4 program (GraphPad Software, Inc). Statistical differences between means were determined using analysis of variance on ranks followed by a post hoc test (Dubbett's comparison procedures) as appropriate. A value of P < 0.05 was considered statistically significant.
Effects of Curcumin and Pioglitazone on Diet Ingestion, Hypertriglyceridemia, Hepatic Steatosis, and PPARα Expression Reduction in Fructose-Fed Rats.
After the initial 4-week fructose consumption, drinking water intake of 102 ± 13.2 mL/24 hours was significantly higher, and daily food intake of 26.9 ± 0.8 g/24 hours was contrastively lower in fructose-fed rats than that in control rats (51.8 ± 3.3 mL/24 hours, 29.3 ± 1.2 g/24 hours, respectively). There was no significant difference in water and food intakes among fructose-fed rats receiving vehicle, curcumin, and pioglitazone at week 8 (Fig. 1A). And there was no difference in body weight between control and fructose-fed rats receiving vehicle, curcumin, and pioglitazone (Fig. 1A). Fructose induced hypertriglyceridemia, characterized by high serum levels of TG and VLDL (Fig. 1B-C), as well as high hepatic levels of TG (1.6-fold), VLDL (2.3-fold), and TC (1.4-fold) (Fig. 2A-C) in rats. Curcumin treatment dose-dependently attenuated fructose-induced abnormalities of serum (Fig. 1B-D) and liver (Fig. 2A-C) in rats. Pioglitazone also had significant effects in this model. Slight steatosis and inflammation were observed in the livers of fructose-fed rats, which were completely ameliorated by curcumin and pioglitazone (Fig. 2E).
Increased serum TNF-α levels were reversed by curcumin and pioglitazone (Fig. 1D). In addition, fructose-fed rats showed a significant decrease in hepatic PPARα mRNA levels (Fig. 2D), which was parallel with hepatic VLDL and TG elevation. Both curcumin and pioglitazone restored hepatic PPARα messenger RNA (mRNA) levels in fructose-fed rats (Fig. 2D).
Effects of Curcumin and Pioglitazone on Insulin Resistance and Reduced Hepatic Insulin Sensitivity in Fructose-Fed Rats.
There was no significant change in serum glucose levels between control and fructose-fed rats during the whole experiment (Fig. 3A). Insulin resistance in fructose-fed rats was characterized by increased serum insulin concentrations (Fig. 3B) and decreased insulin sensitivity in ITT and GTT assays (Fig. 3D, E). Curcumin and pioglitazone had significant effects on these changes of fructose-fed rats (Fig. 3B, D, E).
Although there were no significant differences in hepatic basic IR and IRS1 protein levels in control and fructose-fed groups, IR and IRS1 phosphorylation levels were decreased to 46% and 38% of control in the liver of fructose-fed rats, respectively (Fig. 4A, B). Curcumin and pioglitazone reversed fructose-induced reduction of hepatic P-IR and P-IRS1 protein levels in rats (Fig. 4A, B).
Effects of Curcumin and Pioglitazone on Impaired Activation of Hepatic Akt and ERK 1/2 in Fructose-Fed Rats.
In parallel with IRS1 phosphorylation reduction, although there was no change in hepatic basic Akt protein levels, decreased Akt phosphorylation was observed in fructose-fed rats (Fig. 4C). Curcumin and pioglitazone prevented fructose-induced decrease of hepatic P-Akt protein levels in rats (Fig. 4C). P-ERK1/2 protein levels were also reduced in the livers of fructose-fed rats (Fig. 4D), which was attenuated by curcumin (Fig. 4D), but not pioglitazone (Fig. 4D).
Effects of Curcumin and Pioglitazone on Hyperleptinemia and Impaired Hepatic Leptin Signaling Transduction in Fructose-Fed Rats.
High serum leptin levels in fructose-fed rats were reduced by curcumin and pioglitazone (Fig. 3C). Leptin binding to the long form of leptin receptor (ObRL) induces phosphorylation and activation of JAK2, as well as phosphorylation of two Tyr residues, Tyr985 and Tyr1138, in the cytosolic tail of the receptor.25 Hepatic ObRLand its Tyr1138-phosphorylation protein levels were increased in response to high leptin levels in fructose-fed rats (Fig. 5A). Curcumin and pioglitazone inhibited these sustained increases in hepatic ObRL and P-Tyr1138-ObRL in fructose-fed rats (Fig. 5A). However, the hepatic Tyr985-phosphorylation level of ObRLwas not changed in fructose-fed rats treated with vehicle, curcumin, or pioglitazone (Fig. 5A). Furthermore, fructose ingestion did not alter JAK2 mRNA or protein levels (Fig. 5B, C), but induced P-JAK2 protein reduction in the livers of rats (Fig. 5C). Curcumin and pioglitazone increased P-JAK2 protein levels in fructose-fed rats (Fig. 5C).
Fructose ingestion did not change STAT3 mRNA and protein levels in rat liver (Fig. 6A, B). Increased hepatic Tyr705 phosphorylation of STAT3 was observed in fructose-fed rats (Fig. 6B). Curcumin, but not pioglitazone, reduced hepatic P-Tyr705-STAT3 protein levels in fructose-fed rats (Fig. 6B). Furthermore, hepatic SOCS3 mRNA and protein levels were increased approximately 1.3-fold and 1.5-fold in fructose-fed rats (Fig. 6C, D), which were attenuated by curcumin. However, pioglitazone had no effect on SOCS3 in this study (Fig. 6C, D).
Effects of Curcumin and Pioglitazone on Hepatic PTP1B Expression and Activity in Fructose-Fed Rats.
To determine whether PTP1B may be involved in curcumin's effects on impairment of liver insulin and leptin signaling transduction in fructose-fed rats, we examined hepatic PTP1B expression and activity. Fructose-fed rats showed higher expression levels of hepatic PTP1B mRNA and protein than normal rats (Fig. 7A, B). Hepatic PTP1B activity in fructose-fed rats was significantly increased by almost twofold compared with that in normal animals (Fig. 7C). Remarkably, curcumin and pioglitazone reduced PTP1B expression (Fig. 7A, B) and activity (Fig. 7C) in the liver of fructose-fed rats.
Basic and clinical studies have proposed curcumin as a therapeutic option for the development and progression of NASH.18, 19 Information on curcumin's prevention of high dietary fructose-induced hepatic steatosis, however, is still limited. In the present study, fructose-fed rats showed hyperinsulinemia, hyperleptinemia, insulin and leptin resistance with concomitant hepatic steatosis. Curcumin reduced serum levels of TG and VLDL, and hepatic levels of TG, VLDL, and TC, with improvement of whole-body and liver insulin and leptin sensitivity, and attenuation of hepatic steatosis in fructose-fed rats. These data were consistent with other reports that curcumin prevented hyperlipidemia by enhancing insulin or leptin sensitivity in high-fat-fed hamsters20 and experimental type 2 diabetic rats.26 Pioglitazone has therapeutic efficacy in patients with NASH.23 In this study, pioglitazone also showed beneficial effects on fructose-fed rats.
Insulin, as a well-known regulator of lipid and lipoprotein metabolism, tightly controls hepatic lipogenesis and lipoprotein production.27 The current study confirmed that IRS1 Tyr phosphorylation reduction was responsible for decreased activation of Akt and ERK1/2, exhibiting defective insulin signaling transduction, with reduced PPARα expression and increased VLDL production and TG synthesis in the liver of fructose-fed rats. PPARα activators improve insulin sensitivity.28 Curcumin increases phosphorylated Akt and ERK1/2 levels in rodent cortical neurons.29 We found that curcumin enhanced IR and IRS1 Tyr phosphorylation, to activate the Akt and ERK1/2 pathways, and elevated PPARα expression in the liver of fructose-fed rats. These results suggest that curcumin reduces liver VLDL overproduction and TG hypersynthesis through its activation of hepatic insulin signaling transduction and improvement of insulin resistance in fructose-fed rats.
Leptin stimulates activation of JAK2, which also initiates the Akt and ERK1/2 pathways.25 Fructose-induced hyperleptinemia indicates leptin resistance in rats.5, 6 We also found that fructose ingestion aggravated impairment of hepatic leptin signaling transduction characterized by decreasing hepatic Tyr phosphorylation of JAK2, which was consistent with reduced phosphorylation of Akt and ERK1/2 in the liver of fructose-fed rats. Conversely, leptin signaling is transmitted mainly by the STAT pathway and terminated by induction of SOCS3, which, in turn, negatively regulates JAK2.25, 30 Increased STAT activation and SOCS3 expression block JAK2 activation and reduce PPARα activity in fructose-fed rats.5, 6 We also demonstrated that high leptin levels stimulated ObRL expression, activated Tyr1138-ObRL and STAT3 phosphorylation, and increased SOCS3 expression in the liver of fructose-fed rats. Direct overexpression of SOCS3 in the liver by adenoviral-mediated gene transfer markedly decreases Tyr phosphorylation of IRS1.31 These observations indicate that hepatic defective leptin signaling via impairment of Akt and ERK1/2 pathway may be related to the lack of PPARα expression, subsequently leading to hypertriglyceridemia and hepatic steatosis in the liver of fructose rats. Curcumin interrupts leptin signaling by reducing ObRL phosphorylation and abrogates the stimulatory effect of leptin on hepatic stellate cell activation.20 It also inhibits STAT phosphorylation and SOCS3 expression in rat pancreatic islets.32 The current study found that curcumin increased hepatic JAK2 phosphorylation, as well as suppressed P-Tyr1138-ObRL and P-STAT3, then down-regulated SOCS3 expression, exhibiting improvement of hepatic leptin signaling transduction and reduction of liver VLDL overproduction and TG hypersynthesis in the leptin-resistant state of fructose-fed rats. Pioglitazone also increased Tyr phosphorylation of IRS1 and JAK2 and stimulated Akt activation but failed to alter STAT3 and SOCS3 in fructose-fed rats. Thus, SOCS3 inhibition of curcumin partially participates in its improvement of insulin and leptin signaling transduction associated with stimulation of PPARα expression and reduction of VLDL overproduction and TG hypersynthesis in the liver of fructose-fed rats.
PTP1B is a major negative regulator of both insulin and leptin signaling. PTP1B hyperexpression reduces Tyr phosphorylation of IR and IRS in rat Fao hepatoma cells33 and decreases ERK phosphorylation in Michigan Cancer Foundation-7 (MCF-7) cells.34 Overexpression of hepatic PTP1B is observed in fructose-fed harmers with hepatic insulin resistance and VLDL overproduction.15, 16 The current study found that fructose-fed rats displayed significant increases in hepatic PTP1B expression and activity, suggesting that hyperexpression of PTP1B targeting IRS1 and JAK2 dephosphorylates Tyr residues of key proteins in insulin and leptin signaling transduction, leading to reduced activation of Akt and ERK1/2 in the liver of fructose-fed rats. PTP1B antisense oligonucleotide lowers PTP1B protein, improves hepatic insulin sensitivity, and reduces hepatic lipid accumulation in diabetic mice.35, 36 PTP1B inhibitors can improve insulin and leptin sensitivity37, 38 and reduce blood TG and TC levels in obese adolescent rats.39 The current study for the first time demonstrated that curcumin and pioglitazone inhibited hepatic PTP1B expression and activity, which was parallel with its improvement of insulin and leptin signaling transduction in fructose-fed rats. This finding provides solid evidence that inhibition of hepatic PTP1B plays an important role in the reduction of hepatic VLDL overproduction and TG hypersynthesis in fructose-fed rats. Therefore, PTP1B is a very important target for curcumin therapy for hypertriglyceridemia and liver steatosis induced by high fructose consumption.
In summary, we firstly demonstrated that curcumin targeting hepatic PTP1B prevented fructose-induced hypertriglyceridemia and hepatic steatosis by enhancement of hepatic insulin and leptin sensitivity in rats. The ability of curcumin to inhibit hepatic PTP1B hyperexpression resulted in hepatic insulin and leptin signaling improvement characterized by an increase in IR, IRS1, and JAK2 phosphorylation with suppression of STAT3 activation and SOCS3 expression, and activation of the Akt and ERK 1/2 pathways, correlated with increase of PPARα expression and subsequent reduction of VLDL overproduction and TG hypersynthesis in the liver of fructose-fed rats. The hypothetical mechanisms by which curcumin prevent hypertriglyceridemia and hepatic steatosis in fructose-fed rats are summarized in Fig. 8. These data further support evidence that inhibition of hepatic PTP1B contributes to the improvement of insulin and leptin resistance. Curcumin may have therapeutic application to prevent fructose-induced insulin and leptin-resistant states occurring in hepatic steatosis.
The authors thank Chuang Wang, Xing Wang, Yu-Jie Lou, and Ju Wang for kind assistance in the animal studies.