Background Non-alcoholic fatty liver disease (NAFLD) is a common hepatic disease with an increasing prevalence but an unclear aetiology. This study aimed to investigate the functional implications of microRNA-122 (miR-122) in the pathogenesis of NAFLD and the possible molecular mechanisms. Methods Both in vitro and in vivo models of NAFLD were generated by treating HepG2 and Huh-7 cells with free fatty acids (FFA) and by feeding mice a high-fat diet (HFD), respectively. HE and Oil Red O staining were used to examine liver tissue morphology and lipid deposition, respectively. Immunohistochemical (IHC) staining was used to examine Sirt1 expression in liver tissues. qRT-PCR and Western blotting were employed to measure the expression of miR-122, Sirt1, and proteins involved in lipogenesis and the AMPK pathway. Enzyme-linked immunosorbent assay (ELISA) was used to quantify triglyceride (TG) levels in HepG2 and Huh-7 cells and in liver tissues. The interaction between miR-122 and the Sirt1 gene was further examined by a dual luciferase reporter assay and RNA-immunoprecipitation (RIP). Results NAFLD hepatic tissues and FFA-treated HepG2 and Huh-7 cells presented excess lipid production and TG secretion, accompanied by miR-122 upregulation, Sirt1 downregulation, and potentiated lipogenesis-related genes. miR-122 suppressed Sirt1 expression via binding to its 3′-untranslated region (UTR). Knockdown of miR-122 effectively mitigated excessive lipid production and suppressed the expression of lipogenic genes in FFA-treated HepG2 and Huh-7 cells via upregulating Sirt1. Furthermore, miR-122 knockdown activated the LKB1/AMPK signalling pathway. Conclusion The inhibition of miR-122 protects hepatocytes from lipid metabolic disorders such as NAFLD and suppresses lipogenesis via elevating Sirt1 and activating the AMPK pathway. These data support miR-122 as a promising biomarker and drug target for NAFLD.

Early cardioprotection can be achieved by a brief ischaemia of noncardiac tissues. Our study examined whether a brief ischaemia of the small intestine induces both early and delayed cardioprotection in the rabbit and assessed the possible mechanism involved in the activation of capsaicin-sensitive sensory nerves. The plasma concentration of creatine kinase (CK) and infarct size (necrotic zone/left ventricular zone) after 30 min coronary artery occlusion and 180 min reperfusion were determined in rabbits. Infarct size was 35.5+/-6.8% in the control non-preconditioned group. Preconditioning induced by a brief period of 10-min small intestine ischaemia significantly reduced infarct size (6.5+/-1.9%, P<0.01 vs. the control non-preconditioned group) and decreased CK release (3092+/-236 and 1094+/-117 U/l for myocardial ischaemia-reperfusion and preconditioning plus myocardial ischemia-reperfusion, respectively, P<0.01), and the protection was partly abolished by pretreatment with capsaicin (50 mg/kg, s.c.) 4 days before the experiments. A brief period of anterior mesenteric artery occlusion caused an increase in the plasma level of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), an effect which was abolished by pretreatment with capsaicin. Similar protection was shown in the animals subjected to a brief period of anterior mesenteric artery occlusion 24 h before coronary artery occlusion, and this delayed protection was also abolished partly by pretreatment with capsaicin. Capsaicin treatment (50 mg/kg, s.c.) alone also protected the ischaemic myocardium. The results suggest that brief ischaemia of the small intestine induces both early and delayed protection against reperfusion-induced myocardial injury, and the effects are, at least partly, related to the activation of capsaicin-sensitive sensory nerves.

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Rationale: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism, however, the molecular pathways underlying this effect are incompletely understood. Objective: We sought to determine the role of hepatic glucagon receptor (Gcgr) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms. Methods and Results: We show that Gcgr signaling plays an essential role in low-density lipoprotein (LDL) cholesterol homeostasis through regulating the proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDL receptor protein and increased plasma LDL-cholesterol. Conversely, treatment of WT mice with glucagon lowered LDL-cholesterol levels, whereas this response was abrogated in Pcsk9−/− and Ldlr−/− mice. Our gain- and loss-of-function studies identified exchange protein activated by cAMP-2 (Epac2) and Ras-related protein-1 (Rap1) as the downstream mediators of glucagon’s action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation. Conclusions: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new post-transcriptional mechanism of PCSK9 regulation.

To explore whether rosiglitazone (RSG), a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist, exerts beneficial effects on endothelial dysfunction induced by homocysteine thiolactone (HTL) and to investigate the potential mechanisms. Incubation of cultured human umbilical vein endothelial cells with HTL (1 mM) for 24 hrs significantly reduced cell viabilities assayed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, as well as enhanced productions of reactive oxygen species, activation of nuclear factor kappa B, and increased intercellular cell adhesion molecule-1 secretion. Pre-treatment of cells with RSG (0.001–0.1 mM), pyrollidine dithiocarbamate (PDTC, 0.1 mM) or apocynin (0.1 mM) for 1 hr reversed these effects induced by HTL. Furthermore, co-incubation with GW9662 (0.01 mM) abolished the protective effects of RSG on HTL-treated cells. In ex vivo experiments, exposure of isolated aortic rings from. rats to HTL (1 mM) for 1 hr dramatically impaired acetylcholine-induced endothelium-dependent relaxation, reduced release of nitric oxide and activity of superoxide dismutase, and increased malondialdehyde content in aortic tissues. Preincubation of aortic rings with RSG (0.1, 0.3, 1 mM), PDTC or apocynin normalized the disorders induced by HTL. In vivo analysis indicated that administration of RSG (20 mg/kg/d) remarkably suppressed oxidative stress and prevented endothelial dysfunction in rats fed HTL (50 mg/kg/d) for 8 weeks. RSG improves endothelial functions in rats fed HTL, which is related to PPARγ-dependent suppression of oxidative stress.

Prevalence of hypertension in Sichuan Tibetan was significantly higher than the national level with low rates of awareness, treatment, and control of hypertension. Intervention measurements are needed to change some unhealthy lifestyles, behaviors, and habits in this region.

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