Curcumin Attenuates Diet‐Induced Hepatic Steatosis by Activating AMP‐Activated Protein Kinase

Curcumin is a well‐known component of traditional turmeric (Curcuma longa), which has been reported to prevent obesity and diabetes. However, the effect of curcumin on hepatic lipid metabolism remains unclear. The aim of this study was to examine the effects of curcumin on hepatic steatosis in high‐fat/cholesterol diet (HFD)‐induced obese mice. Male C57BL/6J mice were fed a normal diet (ND), HFD or HFD with 0.15% curcumin (HFD+C) for 11 weeks. We found that curcumin significantly lowered the body‐weight and adipose tissue weight of mice in the HFD+C group compared with the findings for the HFD group (p < 0.05). The levels of total cholesterol, fasting glucose and insulin in serum were decreased, and HFD‐induced impairment of insulin sensitivity was improved by curcumin supplementation (p < 0.05). Curcumin protected against the development of hepatic steatosis by reducing hepatic fat accumulation. Moreover, curcumin activated AMP‐activated protein kinase (AMPK) and elevated the gene expression of peroxisome proliferator‐activated receptor alpha. By contrast, curcumin suppressed the HFD‐mediated increases in sterol regulatory element‐binding protein‐1, acetyl‐CoA carboxylase 1, fatty acid synthase and cluster of differentiation 36 expression. Taken together, these findings indicate that curcumin attenuates HFD‐induced hepatic steatosis by regulating hepatic lipid metabolism via AMPK activation, suggesting its use as a therapeutic for hepatic steatosis.     

Thiazolidinediones improve hepatic fibrosis in rats with non‐alcoholic steatohepatitis by activating the adenosine monophosphate‐activated protein kinase signalling pathway

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Resveratrol protects against hepatic insulin resistance in a rat's model of non‐alcoholic fatty liver disease by down‐regulation of GPAT‐1 and DGAT2 expression and inhibition of PKC membranous translocation

Non‐alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance (IR). Resveratrol (RES) a potent hypolipidemic dietary polyphenol has been identified for its ability to prevent hepatic steatosis and hepatic IR in high‐fat diet (HFD)‐fed murine models of NAFLD. In the present study, we have carried an in vivo animal experiment to identify a novel mechanism for RES protective action. Sub‐chronic (45 days) RES pretreatment in 3 days HFD‐fed adult Wistar rats prevented early hepatic IR through inhibiting PKC/JNK activation; decreasing p‐IRS (Ser³⁰⁷) and increasing p‐IRS(Tyr⁶¹²), p‐Akt(Ser⁴⁷³) and p‐GSK3(Ser⁹). These effects of RES were associated with reduced expression of acyl‐CoA:glycerol‐sn‐3‐phosphate acyltransferase (GPAT‐1) and diacylglycerol:acyl‐CoA acyltransferase (DGAT2), two critical enzymes in the glycerol‐3‐phosphate pathway for de novo triglycerides synthesis. These data indicate that RES protects against NAFLD, initially, by inhibiting the early development of hepatic IR.     

Alleviative effect of ciliary neurotrophic factor analogue on high fat‐induced hepatic steatosis is partially independent of the central regulation

Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high‐fat diet‐fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat‐induced hepatic steatosis. The rat model of fatty liver was induced by a high‐fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05‐0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT‐1 and PPARα, and decreased SREBP‐1c, FAS and SCD‐1 in steatotic HepG2 cells. But the production of nitric oxide and 8‐isoPGF_2α in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat‐induced hepatic steatosis.     

Changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis induced by an acetyl‐l‐carnitine and nicotinamide treatment in dyslipidaemic insulin‐resistant rats

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Ferulic acid improves lipid and glucose homeostasis in high‐fat diet‐induced obese mice

Ferulic acid (FA) is a plant phenolic acid that has several pharmacological effects including antihyperglycaemic activity. Thus, the objective of this study is to investigate the effect of FA on glucose and lipid metabolism in high‐fat diet (HFD)‐induced obese mice. Institute for Cancer Research (ICR) mice were fed a HFD (45 kcal% fat) for 16 weeks. At the ninth week of induction, the obese mice were orally administered with daily FA doses of 25 and 50 mg/kg for the next eight weeks. The results show that FA significantly reduced the elevated blood glucose and serum leptin levels, lowered the insulin resistance, and increased the serum adiponectin level. Moreover, serum lipid level, and liver cholesterol and triglyceride accumulations were also reduced. The histological examination showed clear evidence of a decrease in the lipid droplets in liver tissues and smaller size of fat cells in the adipose tissue in the obese mice treated with FA. Interestingly, FA reduced the expression of hepatic lipogenic genes such as sterol regulatory element‐binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl‐CoA carboxylase (ACC). It could also up‐regulate hepatic carnitine palmitoyltransferase 1a (CPT1a) gene and peroxisome proliferator‐activated receptor alpha (PPARα) proteins. The FA treatment was also found to suppress the protein expressions of hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxylase (PEPCK) and glucose‐6‐phosphatase (G6Pase). In conclusion, the findings of this study demonstrate that FA improves the glucose and lipid homeostasis in HFD‐induced obese mice probably via modulating the expression of lipogenic and gluconeogenic genes in liver tissues.     

Chronic consumption of a high‐fat diet rich in corn oil activates intrinsic cell death pathway and induces several ultrastructural changes in the atria of healthy and type 1 diabetic rat

This study investigates the effect of chronic consumption of a high‐fat diet rich in corn oil (CO‐HFD) on atrial cells ultrastructure, antioxidant levels and markers of intrinsic cell death of both control and type 1 diabetes mellitus (T1DM)‐induced rats. Adult male rats (10 rats/group) were divided into four groups: control fed standard diet (STD) (3.82 kcal/g, 9.4% fat), CO‐HFD (5.4 kcal/g, 40% fat), T1DM fed STD, and T1DM + CO‐HFD. CO‐HFD and T1DM alone or in combination impaired systolic and diastolic functions of rats and significantly reduced levels of GSH and the activity of SOD, enhanced lipid peroxidation, increased protein levels of P53, Bax, cleaved caspase‐3, and ANF and decreased levels of Bcl‐2 in their atria. Concomitantly, atrial cells exhibited fragmentation of the myofibrils, disorganized mitochondria, decreased number of atrionatriuretic factor (ANF) granules, and loss of gap junctions accompanied by changes in capillary walls. Among all treatments, the severity of all these findings was more severe in T1DM and most profound in the atria of T1DM + CO‐HFD. In conclusion, chronic consumption of CO‐HFD by T1DM‐induced rats elicits significant biochemical and ultrastructural damage to rat atrial cells accompanied by elevated oxidative stress and mitochondria‐mediated cell death.     

Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high‐cholesterol‐fed rats

This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high‐cholesterol‐fed rats. Male Sprague‐Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high‐cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high‐cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine‐treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine‐conjugated bile acids by 61% and decreased glycine‐conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine‐conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α‐hydroxylase (CYP7A1), the rate‐limiting enzyme for bile acid synthesis, by three‐ and two‐fold, respectively. Taurine also decreased the enzymatic activity of acyl‐CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine‐conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels.     

Cassia tora (Leguminosae) seed extract alleviates high-fat diet-induced nonalcoholic fatty liver

The aim of this study was to examine the effects of Cassia tora seeds on high-fat diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. After being fed a HFD for two weeks, rats were orally dosed with Cassia seed ethanol extract (CSEE) (100, 200, or 300 mg/kg) once daily for 8 weeks. CSEE induced dose-dependent reductions in plasma lipid levels, as well as decreased the over hepatic lipid accumulation. Furthermore, CSEE treatment improved HFD-induced hepatic histological lesions. CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated the gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the livers of HFD-fed rats. AMPK inhibition by compound C retarded CSEE-induced reduction in triglyceride accumulation in HepG2 cells stimulated by insulin. Our findings suggest that CSEE may regulate hepatic lipid homeostasis related with an AMPK-dependent signaling pathway. Targeting AMPK activation with CSEE may represent a promising approach for the prevention and treatment of obesity-related non-alcoholic fatty liver disease.     

Exercise training protects against atherosclerotic risk factors through vascular NADPH oxidase,extracellular signal‐regulated kinase 1/2 and stress‐activated protein kinase/c‐Jun N‐terminal kinase downregulation in obese rats

Exercise training reverses atherosclerotic risk factors associated with metabolic syndrome and obesity. The aim of the present study was to determine the molecular anti‐inflammatory, anti‐oxidative and anti‐atherogenic effects in aorta from rats with high‐fat diet‐induced obesity. Male Sprague‐Dawley rats were placed on a high‐fat (HFD) or control (CD) diet for 12 weeks. The HFD rats were then divided into four groups: (i) sedentary HFD‐fed rats (HFD‐S); (ii) exercise trained (motor treadmill 5 days/week, 60 min/day, 12 weeks) HFD‐fed rats (HFD‐Ex); (iii) modified diet (HFD to CD) sedentary rats (HF/CD‐S); and (iv) an exercise‐trained modified diet group (HF/CD‐Ex). Tissue levels of NADPH oxidase (activity and expression), NADPH oxidase (Nox) 1, Nox2, Nox4, p47^phox, superoxide dismutase (SOD)‐1, angiotensin AT₁ and AT₂ receptors, phosphorylated mitogen‐activated protein kinase (MAPK; extracellular signal‐regulated kinase (ERK) 1/2, stress‐activated protein kinase (SAPK)/c‐Jun N‐terminal kinase (JNK)) and vascular cell adhesion molecule‐1 (VCAM‐1) were determined in the aorta. Plasma cytokines (tumour necrosis factor (TNF)‐α and interleukin (IL)‐6) levels were also measured. Obesity was accompanied by increases in NADPH oxidase activity, p47^phox translocation, Nox4 and VCAM‐1 protein expression, MAPK (ERK1/2, SAPK/JNK) phosphorylation and plasma TNF‐α and IL‐6 levels. Exercise training and switching from the HFD to CD reversed almost all these molecular changes. In addition, training increased aortic SOD‐1 protein expression and decreased ERK1/2 phosphorylation. These findings suggest that protective effects of exercise training on atherosclerotic risk factors induced by obesity are associated with downregulation of NADPH oxidase, ERK1/2 and SAPK/JNK activity and increased SOD‐1 expression.     

Maternal fructose intake during pregnancy modulates hepatic and hypothalamic AMP‐activated protein kinase signalling in a sex‐specific manner in offspring

Dietary fructose ingestion during gestation affects carbohydrate metabolism in the offspring. In the present study, we investigated the effects of excess fructose intake during pregnancy on hepatic and hypothalamic AMP‐activated kinase (AMPK) expression and phosphorylation, as well as hepatic glucose‐6‐phosphatase (G6Pase) activity in offspring. Pregnant Wistar rats received normal chow and 100 g/L fructose solution or normal water during gestation ad libitum. On gestational Day 21, some dams were killed and plasma samples and fetuses were collected. The remaining dams received normal water after spontaneous delivery during lactation. Pups were killed on postnatal Day 22 and the plasma, liver and hypothalamus were collected and analysed. Plasma glucose and insulin levels increased in female but not male offspring in the fructose group. Although the mRNA and total protein levels of AMPKα were unchanged, levels of phosphorylated AMPKα protein in the fructose group of female offspring were significantly lower in the liver and 4.6‐fold higher in the hypothalamus. The hepatic protein level of sirtuin 1, which is involved in AMPK phosphorylation and activation, was significantly reduced in the fructose group of female offspring. The activity of G6Pase, which plays a role in gluconeogenesis, was significantly enhanced in the liver of female offspring from fructose‐fed dams. These changes were not observed in male offspring. In conclusion, we found that excessively high fructose intake during pregnancy may modulate the hepatic and hypothalamic AMPK signalling pathways in female offspring after birth.     

Knockdown of hepatic aquaglyceroporin-9 alleviates high fat diet-induced non-alcoholic fatty liver disease in rats

Non-alcoholic fatty liver disease (NAFLD) has emerged as a common public health problem that can progress to end-stage liver disease. Although the function of aquaglyceroporin-9 (AQP9) as a glycerol channel has been proven, the mechanism of AQP9 in the development of NAFLD is poorly understood. To investigate the effect of hepatic glycerol uptake inhibition, we utilized a lentivirus-associated RNA interference technique to knock down the expression of hepatic AQP9 in high fat diet (HFD)-induced NAFLD in rodents. Male Sprague–Dawley rats were fed with a standard chow diet or HFD for 8 weeks. Rats fed a HFD were separated into 3 groups: HFD, control and transfection group, which were injected with equivalent amounts of PBS, lentivirus-scramble and lentivirus-shRNA-AQP9 through the hepatic portal vein. The results showed a remarkable decrease in the expression of AQP9 mRNA and protein in liver for the transfection group. Furthermore, less hepatic steatosis occurred when compared to the HFD and control groups after 8 weeks. Our results indicate a potential role for AQP9 in the pathogenesis of hepatic steatosis.     

Camel milk protein hydrosylate alleviates hepatic steatosis and hypertension in high fructose-fed rats

ContextCamel milk is used in traditional medicine to treat diabetes mellitus hypertension and other metabolic disorders.ObjectiveThis study evaluated the antisteatotic and antihypertensive effects of camel milk protein hydrolysate (CMH) in high fructose (HF)-fed rats and compared it with the effects afforded by the intact camel milk protein extract (ICM).Materials and methodsAdult male Wistar rats were divided into 6 groups (n = 8 each) as 1) control, 2) ICM (1000 mg/kg), 3) CMH (1000 mg/kg), 4) HF (15% in drinking water), 5) HF (15%) + ICM (1000 mg/kg), and 6) HF (15%) + CMH (1000 mg/kg). All treatments were given orally for 21 weeks, daily.ResultsBoth ICM and CMH reduced fasting glucose and insulin levels, serum and hepatic levels of cholesterol and triglycerides, and serum levels of ALT and AST, angiotensin II, ACE, endothelin-1, and uric acid in HF-fed rats. In addition, both ICM and CMH reduced hepatic fat deposition in the hepatocytes and reduced hepatocyte damage. This was associated with an increase in the hepatic activity of AMPK, higher PPARα mRNA, reduced expression of fructokinase C, SREBP1, SREBP2, fatty acid synthase, and HMG-CoA-reductase. Both treatments lowered systolic and diastolic blood pressure. However, the effects of CMH on all these parameters were greater as compared to ICM.Discussion and conclusionsThe findings of this study encourage the use of CMH in a large-scale population and clinical studies to treat metabolic steatosis and hypertension.     

Long-term baicalin administration ameliorates metabolic disorders and hepatic steatosis in rats given a high-fat diet

Aim:

Baicalin, one of the major flavonoids in Scutellaria baicalensis, possesses antioxidant and anti-inflammatory properties. However, the effects of baicalin on metabolic disorders and hepatic steatosis have not been investigated.

Methods:

Body weight was examined in high-fat diet (HFD)-fed rats with or without baicalin treatment. At the end of the experiment, serum biochemical parameters, liver histology and lipid profile were analyzed to assess whether the animals were suffering from metabolic disorders or hepatic steatosis. In the liver, the phosphorylation of AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and the gene expression of some enzymes involved in lipogenesis were examined. The effects of baicalin on the phosphorylation of AMPK and lipid accumulation induced by high glucose in human hepatoma HepG2 cells were also examined.

Results:

Baicalin (80 mg/kg) administered ip for 16 weeks suppressed body weight gain in HFD-fed rats. Weight reduction was accompanied by the reduction of visceral fat mass. Baicalin significantly decreased the elevated serum cholesterol, free fatty acid and insulin concentrations caused by the HFD. Baicalin also suppressed systemic inflammation by reducing the serum level of tumor necrosis factor α. Baicalin reduced hepatic lipid accumulation, enhanced the phosphorylation of AMPK and ACC and down-regulated genes involved in lipogenesis, including fatty acid synthase and its upstream regulator SREBP-1c. In HepG2 cells, baicalin (5 and 10 μmol/L) increased the phosphorylation of AMPK and decreased lipid accumulation following the addition of high glucose.

Conclusion:

Our study suggests that baicalin might have beneficial effects on the development of hepatic steatosis and obesity-related disorders by targeting the hepatic AMPK.     

A high‐fat diet and multiple administration of carbon tetrachloride induces liver injury and pathological features associated with non‐alcoholic steatohepatitis in mice

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Mechanism of subchronic vinyl chloride exposure combined with a high-fat diet on hepatic steatosis

Vinyl chloride (VC) is a common industrial organic chlorine and environmental pollutant. In recent years, the dietary structure of residents especially Chinese has gradually shifted to western dietary patterns. VC aggravates dietary fatty acid-induced hepatic steatosis, but its mechanism is still unclear. And if the risk factors for steatosis persist, more severe diseases such as fibrosis and cirrhosis will occur. Therefore, we studied the effects and mechanisms of VC (160 and 800 mg/m³) and its metabolite (chloroacetaldehyde, 2.25, 4.5, and 9 μM) on hepatic steatosis of high-fat diet (HFD)-fed mice and palmitic acid (PA, 100 μM) treated HepG2 cells. Liver and serum biochemical indicators and pathological staining of the liver showed that the hepatic steatosis of VC combined with HFD groups was more severe than that of single-exposure groups (HFD group, low-dose VC group, and high-dose VC group). Moreover, VC enhanced HFD-induced oxidative stress (OS) and endoplasmic reticulum stress (ERS) and further upregulated the expression of sterol regulatory element-binding protein 1 (SREBP-1) and FAS. Besides, antioxidants and ERS inhibitors reduced the steatosis of HepG2 cells induced by VC metabolites and PA. These results suggest that VC exposure can enhance the degree of hepatic steatosis in HFD-fed mice. VC combined with HFD led to OS and ERS and upregulated the expression of de novo lipogenesis-related proteins, which may be related to the occurrence of hepatic steatosis. And the increased expression of CYP2E1 induced by VC combined with HFD may be the cause of OS.     

A novel berberine‐metformin hybrid compound exerts therapeutic effects on obese type 2 diabetic rats

In this study, we investigated the biological activities of a novel berberine‐metformin hybrid compound (BMH473) as an anti‐diabetic agent. BMH473 exhibited significant anti‐hyperglycaemic and anti‐hyperlipidaemic effects on T2DM rats. In white adipose tissue, BMH473 reduced the perirenal and epididymal adipose tissue mass and modulated the lesions in perirenal adipose tissue, by inhibiting the protein expressions of PPAR‐?, C/EBP‐α and SREBP‐1c as well as the mRNA expressions of lipogenic genes. Moreover, BMH473 downregulated the levels of pro‐inflammatory cytokines in perirenal adipose tissue through the suppression of p‐NF‐κB. In liver, BMH473 reduced liver ectopic fat accumulation, by regulating the protein expression levels of SREBP‐1c and PPAR‐α as well as the mRNA expression levels of lipogenic genes. In addition, BMH473 inhibited hepatic gluconeogenesis by promoting the phosphorylation levels of AMPK α and ACC, and down‐regulating the mRNA expression levels of FBPase, G6Pase and PEPCK. Furthermore, BMH473 exhibited significant inhibitory effects on lipogenesis and lipid accumulation in 3T3‐L1 adipocytes by modulating the protein expression levels of PPAR‐?, C/EBP‐α and SREBP‐1 c as well as the mRNA expression levels of lipogenic genes. In conclusion, our results suggest that the newly synthesized BMH473 is beneficial for maintaining glucose and lipid homeostasis in type 2 diabetic rats, and exhibits better anti‐hyperlipidaemic effects compared to metformin and berberine.     

5‐Aminoimidazole‐4‐carboxamide‐1‐β‐d‐ribofuranoside Increases Myocardial Glucose Uptake during Reperfusion and Induces Late Pre‐conditioning: Potential Role of AMP‐Activated Protein Kinase

Abstract: Late pre‐conditioning protects against myocardial ischaemic‐reperfusion injury. AMP‐activated protein kinase (AMPK) is activated by exercise and 5‐aminoimidazole‐4‐carboxamide‐1‐β‐d ‐ribofuranoside (AICAR). Early pre‐conditioning involves AMPK activation and increased myocardial glucose uptake. The aim of the present study was to determine whether AICAR activates myocardial AMPK and induces late pre‐conditioning and whether myocardial glucose uptake during reperfusion was modulated. Twenty‐four hours after AICAR treatment or exercise, Wistar rats were subjected to ischaemia and reperfusion in a Langendorff model and compared to control rats. AMPK activity increased immediately 2.5‐fold in AICAR‐treated animals (P < 0.01) and twofold in exercised animals (P < 0.05). AICAR and exercise reduced infarct size by 60% and 50% (both P < 0.01), respectively, and increased myocardial glucose uptake during reperfusion (AICAR; 45%, P < 0.05, exercise; 40%, P < 0.05). In conclusion, AICAR induces late pre‐conditioning and increases myocardial glucose uptake during reperfusion in rat hearts. AICAR and exercise activate AMPK, suggesting a role of AMPK in the signalling mechanisms behind late pre‐conditioning.