大豆蛋白对高脂饲料喂养大鼠固醇调节元件结合蛋白基因表达的影响

目的探讨大豆蛋白在正常饮食和高脂饮食状态下对大鼠脂代谢相关固醇调节元件结合蛋白(SREBP)基因表达水平的影响。方法 48只清洁级SD大鼠,按体重随机分为4组,分别喂饲含酪蛋白和大豆蛋白的正常饲料和高脂饲料28d后,脱颈椎处死动物,检测激素指标及基因表达水平。结果大豆蛋白组大鼠血清胰岛素水平和胰岛素/胰高血糖素比值显著低于酪蛋白组(P<0.05);大豆蛋白高脂组大鼠血清胰岛素水平显著低于酪蛋白高脂组(P<0.05);大豆蛋白组和大豆蛋白高脂组大鼠肝脏SREBP-1,2基因表达均分别显著低于酪蛋白组和酪蛋白高脂组(P<0.05);大豆蛋白组和大豆蛋白高脂组大鼠肝脏SREBP-1蛋白表达明显低于酪蛋白组和酪蛋白高脂组(P<0.05)。结论大豆蛋白可能通过影响胰岛素进而影响SREBP-1基因表达来调节血脂水平。     

Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis

Recently, hepatic peroxisome proliferator-activated receptor (PPAR)γ has been implicated in hepatic lipid accumulation. We found that the C3H mouse strain does not express PPARγ in the liver and, when subject to a high-fat diet, is resistant to hepatic steatosis, compared with C57BL/6 (B6) mice. Adenoviral PPARγ2 injection into B6 and C3H mice caused hepatic steatosis, and microarray analysis demonstrated that hepatic PPARγ2 expression is associated with genes involved in fatty acid transport and the triglyceride synthesis pathway. In particular, hepatic PPARγ2 expression significantly increased the expression of monoacylglycerol O-acyltransferase 1 (MGAT1). Promoter analysis by luciferase assay and electrophoretic mobility shift assay as well as chromatin immunoprecipitation assay revealed that PPARγ2 directly regulates the MGAT1 promoter activity. The MGAT1 overexpression in cultured hepatocytes enhanced triglyceride synthesis without an increase of PPARγ expression. Importantly, knockdown of MGAT1 in the liver significantly reduced hepatic steatosis in 12-wk-old high-fat-fed mice as well as ob/ob mice, accompanied by weight loss and improved glucose tolerance. These results suggest that the MGAT1 pathway induced by hepatic PPARγ is critically important in the development of hepatic steatosis during diet-induced obesity.     

Discovery of a potent FKBP38 agonist that ameliorates HFD-induced hyperlipidemia via mTOR/P70S6K/SREBPs pathway

The mammalian target of rapamycin (mTOR)-sterol regulatory element-binding proteins (SREBPs) signaling promotes lipogenesis. However, mTOR inhibitors also displayed a significant side effect of hyperlipidemia. Thus, it is essential to develop mTOR-specific inhibitors to inhibit lipogenesis. Here, we screened the endogenous inhibitors of mTOR, and identified that FKBP38 as a vital regulator of lipid metabolism. FKBP38 decreased the lipid content in vitro and in vivo via suppression of the mTOR/P70S6K/SREBPs pathway. 3,5,6,7,8,3ʹ,4ʹ-Heptamethoxyflavone (HMF), a citrus flavonoid, was found to target FKBP38 to suppress the mTOR/P70S6K/SREBPs pathway, reduce lipid level, and potently ameliorate hyperlipidemia and insulin resistance in high fat diet (HFD)-fed mice. Our findings suggest that pharmacological intervention by targeting FKBP38 to suppress mTOR/P70S6K/SREBPs pathway is a potential therapeutic strategy for hyperlipidemia, and HMF could be a leading compound for development of anti-hyperlipidemia drugs.     

The sterol regulatory element‐binding protein 2 is dysregulated by tau alterations in Alzheimer disease

Disturbed neuronal cholesterol homeostasis has been observed in Alzheimer disease (AD) and contributes to the pathogenesis of AD. As the master switch of cholesterol biosynthesis, the sterol regulatory element‐binding protein 2 (SREBP‐2) translocates to the nucleus after cleavage/activation, but its expression and activation have not been studied in AD which is the focus of the current study. We found both a significant decrease in the nuclear translocation of N‐terminal SREBP‐2 accompanied by a significant accumulation of C‐terminal SREBP‐2 in NFT‐containing pyramidal neurons in AD. N‐terminal‐ SREBP‐2 is also found in dystrophic neurites around plaques in AD brain. Western blot confirmed a significantly reduced nuclear translocation of mature SREBP‐2 (mSREBP‐2) in AD brain. Interestingly, reduced nuclear mSREBP‐2 was only found in animal models of tauopathies such as 3XTg AD mice and P301L Tau Tg mice but not in CRND8 APP transgenic mice, suggesting that tau alterations likely are involved in the changes of mSREBP‐2 distribution and activation in AD. Altogether, our study demonstrated disturbed SREBP‐2 signaling in AD and related models, and proved for the first time that tau alterations contribute to disturbed cholesterol homeostasis in AD likely through modulation of nuclear mSREBP‐2 translocation.     

Type 2 diabetes mellitus in metabolic-associated fatty liver disease vs. type 2 diabetes mellitus non-alcoholic fatty liver disease: a longitudinal cohort analysis

Introduction and ObjectivesType 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of "metabolic associated fatty liver disease" (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM.Materials and MethodsThe current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events.Results6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p < 0.001) and all-cause mortality (HR: 1.75, CI: 1.29 to 2.40, p < 0.001).ConclusionsThe identification and treatment of NAFLD in patients with T2DM is a major concern and the premature change to MAFLD results in an over-diagnosis of fatty liver, exaggerated mortality, and morbidity in patients with T2DM. The definition of MAFLD causes further heterogeneity in fatty liver disease/NAFLD.