Abstract
Isolated α,β-dehydromonacolin S (C5) from soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178 was recently shown to exhibit an inhibitory effect against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity in vitro. In this study, we investigated the effects of C5 on lipid-lowering, hepatic steatosis, and hepatic gluconeogenesis in vivo. The control rats received a daily dose of either vehicle or C5 at 10 mg/kg, while the high-fat diet-induced obese (HFD) rats were administered vehicle; 1, 3, or 10 mg/kg C5; or 10 mg/kg lovastatin (LO) for 6 weeks. C5 significantly improved dyslipidemia and diminished liver enzymes, HMGR activity, insulin resistance, and hepatic steatosis, comparable to LO without any hepatotoxicity and nephrotoxicity in HFD rats. A higher efficacy of C5 in lipid-lowering activity and anti-hepatic steatosis was associated with a significant decrease in genes involved in lipid metabolism including sterol regulatory element binding protein (SREBP) 1c, SREBP2, liver X receptor alpha (LXRα), and peroxisome proliferator-activated receptor (PPAR) gamma (PPARγ) together with an increase in the PPAR alpha (PPARα). Correspondingly, C5 was able to down-regulate the lipid transporters cluster of differentiation 36 (CD36) and Niemann-Pick C1 Like 1 (NPC1L1), increase the antioxidant superoxide dismutase gene expression, and decrease the proinflammatory cytokines, tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL-1β). Impairment of hepatic gluconeogenesis and insulin resistance in HFD rats was restored by C5 through down-regulation of the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and the activation of AMP-dependent kinase serine (AMPK) and serine/threonine protein kinase B (Akt). Collectively, this novel C5 may be a therapeutic option for treating dyslipidemia, hepatic steatosis, and reducing potential risk for diabetes mellitus.
Highlights
An imbalance between a high-fat diet (HFD) and internal de novo synthesis was shown to be the primary factor contributing to lipid dyshomeostasis as a consequence of hepatic lipid accumulation and non-alcoholic fatty liver disease (NAFLD), which could develop from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis [1]
C5 Improved the General Characteristics and Biochemical Parameters of HFD-Induced determine the effect of C5 on the liver morphology, hematoxylin and eosin (H&E)
Rats demonstrated significant increases in as calorie cated by the weight normal(BW), shapes ofgain, the hepatocytes, a low liver levelindex, of fat and accumulation, the intake, body liver weight (LW), visceral fat and weight absence of hepatic ballooning, as with the
Summary
An imbalance between a high-fat diet (HFD) and internal de novo synthesis was shown to be the primary factor contributing to lipid dyshomeostasis as a consequence of hepatic lipid accumulation and non-alcoholic fatty liver disease (NAFLD), which could develop from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis [1]. Pharmaceuticals 2021, 14, 375 cholesterol contents, leading to hepatic lipid accumulation [2,3]. A previous study found that sterol regulatory element-binding protein 2 (SREBP2) was upregulated after HFD consumption, resulting in the increased expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme of de novo hepatic cholesterol synthesis, in a mouse model [4]. A recent study indicated that abnormal insulin-induced gene 1 expression, a key suppressor of SREBP activation and an accelerator of HMGR degradation, was involved with NAFLD and diabetic dyslipidemia in both in vitro and in vivo, as well as in obese patients [5]. Modulation of hepatic lipid content, predominantly through key regulators involved in lipid metabolism and transporters, is thought to be the primary target for the prevention of lipid dyshomeostasis and its hepatic complications
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