Abstract
BackgroundAlthough many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet.MethodseNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed.ResultsLipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet.ConclusionsA deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.
Highlights
Many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear
NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); NAFL represents the first phase of NASH, which is characterized by steatosis, and can develop into fatty liver disease with associated inflammation [1]
high-fat diet (HFD) feeding induced the phenotype of metabolic syndrome and the pathogenesis of early-stage NASH After 12 weeks of HFD feeding, the endothelial nitric oxide synthase (eNOS)+/+ and HFD mice had significantly higher body weights, liver weights, and visceral fat weights than the control mice (Table 2)
Summary
Many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. Non-alcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease and is associated with systemic insulin resistance (IR) and metabolic syndrome. NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); NAFL represents the first phase of NASH, which is characterized by steatosis, and can develop into fatty liver disease with associated inflammation [1]. Other factors associated with NAFLD progression remain to be determined
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