WDR76 mediates obesity and hepatic steatosis via HRas destabilization.
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ABSTRACT:
SUBMITTER: Park JC
PROVIDER: S-EPMC6927951 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Key pointsNon-alcoholic fatty liver disease, characterized in part by elevated liver triglycerides (i.e. hepatic steatosis), is a growing health problem. In this study, we found that hepatic steatosis is associated with robust hepatic sympathetic overactivity. Removal of hepatic sympathetic nerves reduced obesity-induced hepatic steatosis. Liver sympathetic innervation modulated hepatic lipid acquisition pathways during obesity.AbstractNon-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized in part by excessive hepatic triglyceride accumulation (i.e. hepatic steatosis), the incidence of NAFLD is increasing - in line with the growing obesity epidemic. The role of the autonomic nervous system in NAFLD remains unclear. Here, we show that chronic hepatic sympathetic overactivity mediates hepatic steatosis. Direct multiunit recordings of hepatic sympathetic nerve activity were obtained in high fat diet and normal chow fed male C57BL/6J mice. To reduce hepatic sympathetic nerve activity we utilized two approaches including pharmacological ablation of the sympathetic nerves and phenol-based hepatic sympathetic nerve denervation. Diet-induced NAFLD was associated with a nearly doubled firing rate of the hepatic sympathetic nerves, which was largely due to an increase in efferent nerve traffic. Furthermore, established high fat diet-induced hepatic steatosis was effectively reduced with pharmacological or phenol-based removal of the hepatic sympathetic nerves, independent of changes in body weight, caloric intake or adiposity. Ablation of liver sympathetic nerves was also associated with improvements in liver triglyceride accumulation pathways including free fatty acid uptake and de novo lipogenesis. These findings highlight an unrecognized pathogenic link between liver sympathetic outflow and hepatic steatosis and suggest that manipulation of the liver sympathetic nerves may represent a novel therapeutic strategy for NAFLD.
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Project description:Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.
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