Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide and can develop to nonalcoholic steatohepatitis and later hepatic cirrhosis with a high prevalence to hepatocellular carcinoma. Oxidative stress and chronic hepatic inflammation are implicated in the pathogenesis of NAFLD. MicroRNA-137-3p (miR-137-3p) are associated with oxidative stress and inflammation; however, its role and mechanism in NAFLD remain unclear. Mice were fed with a high-fat diet (HFD) for 24 weeks to establish the NAFLD model. To overexpress or suppress hepatic miR-137-3p expression, mice were intraperitoneally injected with the agomir, antagomir, or respective controls of miR-137-3p at a dose of 100 mg/kg weekly for 6 consecutive weeks before the mice were sacrificed. To validate the involvement of AMP-activated protein kinase alpha (AMPKα) or cAMP-specific phosphodiesterase 4D (PDE4D), HFD mice were intraperitoneally injected with 20 mg/kg compound C or 0.5 mg/kg rolipram every other day for 8 consecutive weeks before the mice were sacrificed. Hepatic miR-137-3p expression was significantly decreased in mice upon HFD stimulation. miR-137-3p agomir alleviated, while miR-137-3p antagomir facilitated HFD-induced oxidative stress, inflammation, and hepatic dysfunction in mice. Mechanistically, we revealed that miR-137-3p is directly bound to the 3′-untranslated region of PDE4D and subsequently increased hepatic cAMP level and protein kinase A activity, thereby activating the downstream AMPKα pathway. In summary, miR-137-3p improves NAFLD through activating AMPKα and it is a promising therapeutic candidate to treat NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized as metabolic disorder and hepatic steatosis and emerges as one of the most common chronic liver diseases worldwide that can develop to nonalcoholic steatohepatitis (NASH) and later hepatic cirrhosis with a high prevalence to hepatocellular carcinoma [1,2,3,4]
The NAFLD model was established by feeding mice with a high-fat diet (HFD) (60% kcal fat, 20% kcal carbohydrates, and 20% kcal protein) for 24 weeks, whereas the matched mice were maintained on a ND [27]
We prove that miR-137-3p agomir ameliorates high-fat diet- (HFD-)induced NAFLD through activating AMPKα
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized as metabolic disorder and hepatic steatosis and emerges as one of the most common chronic liver diseases worldwide that can develop to nonalcoholic steatohepatitis (NASH) and later hepatic cirrhosis with a high prevalence to hepatocellular carcinoma [1,2,3,4]. During the simple hepatic steatosis stage, overwhelming nonestesterified fatty acids (NEFAs) in the hepatocytes destroy the electron transport chain and impair mitochondrial function, eventually leading to the accumulation of excessive reactive oxygen species (ROS) [7] These NEFAs and the intracellular substances released from the injured hepatocytes activate the intrahepatic Kupffer cells, recruit the infiltration of other leukocytes, and generate a proinflammatory microenvironment, thereby facilitating the progression of NAFLD. Qu et al showed that AMPKα activation by gastrodin increased the expression and nuclear translocation of intrahepatic NRF2 and subsequently ameliorated oxidative stress and inflammatory response in NAFLD rodents [13]. Genetic liver-specific AMPKα activation significantly reduced hepatic steatosis and inflammation, thereby alleviating high-fat diet- (HFD-) induced NAFLD [16]. We tried to investigate the role and molecular basis of miR-137-3p in NAFLD
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