Liver steatosis and increased ChREBP expression in mice carrying a liver specific SIRT1 null mutation under a normal feeding condition

SIRT1, a homolog of yeast Sir2, is a type III NAD(+) dependent histone and protein deacetylase. Previous studies of mice carrying liver specific deletion of exon 4 of the Sirt1 gene revealed opposite responses of mutant mice to a high-fat diet in terms of fatty liver formation, which obscures the function of SRIT1 in liver development and lipid metabolism. To investigate this, we deleted exons 5 and 6 of Sirt1 in the liver by using a Cre-loxP approach. Western blot using an antibody to N-terminal SIRT1 does not detect a truncated protein in the liver of the mutant mice (Sirt1(flox5-6/flox5-6);Alb-Cre), suggesting a null mutation for SIRT1 is generated in the liver. Unlike the previously reported phenotypes, the Sirt1(flox5-6/flox5-6);Alb-Cre mice develop fatty liver under a normal feeding condition. The disease starts at two months of age and incidence increases as the animals become older, affecting 78% of them when they are over one year of age. We showed that the steatosis is accompanied by altered expression of a number of genes, including increased expression of ChREBP, which acts as one of the central determinants of lipid synthesis in the liver. This data uncovers an important role of SIRT1 in regulating lipid metabolism in the liver, and the SIRT1 mutant mice may serve as an animal model for studying human fatty liver disease and facilitate the development of effective therapeutic approach for the disease.     

Replacing dietary glucose with fructose increases ChREBP activity and SREBP-1 protein in rat liver nucleus

Diets high in fructose cause hypertriglyceridemia and insulin resistance in part due to simultaneous induction of gluconeogenic and lipogenic genes in liver. We investigated the mechanism underlying the unique pattern of gene induction by dietary fructose. Male Sprague-Dawley rats (n = 6 per group) were meal-fed (4 h/d) either 63% (w/w) glucose or 63% fructose diet. After two weeks, animals were killed at the end of the last meal. Nuclear SREBP-1 was 2.2 times higher in fructose-fed rats than glucose-fed rats. Nuclear FoxO1 was elevated 1.7 times in fructose group, but did not reach significance (P = 0.08). Unexpectedly, no difference was observed in nuclear ChREBP between two groups. However, ChREBP DNA binding was 3.9× higher in fructose-fed animals without an increase in xylulose-5-phospate, a proposed ChREBP activator. In conclusion, the gene induction by dietary fructose is likely to be mediated in part by simultaneously increased ChREBP activity, SREBP-1 and possibly FoxO1 protein in nucleus.     

Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes

Fibroblast growth factor 21 (FGF21) has beneficial effects of improving the plasma glucose and lipid profiles in diabetic rodents. Here, we investigated carbohydrate response element binding protein (ChREBP) involvement in the regulation of FGF21 mRNA expression in liver. Glucose stimulation and adenoviral overexpression of dominant active ChREBP increased FGF21 mRNA. Consistently, adenoviral expression of dominant negative Mlx inhibited glucose induction of FGF21 mRNA. Furthermore, deletion studies of mouse FGF21 gene promoter (−2000 to +65 bp) revealed a glucose responsive region between −74 and −52 bp. These findings suggest that FGF21 expression is regulated by ChREBP.     

A pilot study of the effects of chromium picolinate supplementation on serum fetuin-A,metabolic and inflammatory factors in patients with nonalcoholic fatty liver disease: A double-blind,placebo-controlled trial

BackgroundEvaluating the impact of chromium picolinate supplementation on glycemic status, lipid profile, inflammatory markers and fetuin-A in patients with non-alcoholic fatty liver disease (NAFLD).MethodsIn present research, participants (N = 46) were randomized to (400 mcg/day, n = 23) chromium picolinate and placebo (n = 23) for 3 months.ResultsGlucose indices, and lipid profiles, inflammatory biomarker and fetuin-A were measured before and after the intervention. Chromium reduced triglyceride (TG), atherogenic index of plasma (AIP), very-low-density lipoprotein (VLDL), insulin, homeostatic model assessment for insulin resistance (HOMA-IR), high-sensitivity C-reactive protein (hs-CRP), interleukin (IL) -6, tumor necrosis factor-alpha (TNF-α) and fetuin-A significantly compared to placebo group (p < 0.05). Furthermore, chromium significantly increased the quantitative insulin sensitivity check index (QUICKI). There were no significant differences in total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), fasting blood sugar (FBS), Hemoglobin A1c (HbA1C), interleukin (IL)-17 between the two groups (p < 0.05).ConclusionChromium picolinate significantly decreased TG, insulin, HOMA-IR, fetuin-A, the number of inflammatory factors, and increased QUICKI without changing FBS, HbA1C, TC, LDL, HDL, IL-17 levels and liver steatosis intensity in patients with NAFLD. Further studies by examining the effect of different doses of chromium and mechanisms of cellular action, would help further clarify the subject.     

Discovery of piperidine-aryl urea-based stearoyl-CoA desaturase 1 inhibitors

A series of structurally novel stearoyl-CoA desaturase1 (SCD1) inhibitors has been identified via molecular scaffold manipulation. Preliminary structure–activity relationship (SAR) studies led to the discovery of potent, and orally bioavailable piperidine-aryl urea-based SCD1 inhibitors. 4-(2-Chlorophenoxy)-N-[3-(methyl carbamoyl)phenyl]piperidine-1-carboxamide 4c exhibited robust in vivo activity with dose-dependent desaturation index lowering effects.