Study on the novel molecular mechanism of non-alcoholic fatty liver disease

Abstract

The prevalence of obesity has emerged as the host of metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD). NAFLD is described as the accumulation of excessive lipids within hepatocytes. Many reports demonstrated that 90% of obese patients in U.S. have in the state of fatty liver, covering from hepatic steatosis to much more severe forms of NASH (non-alcoholic steatohepatitis), which can induce fibrosis, cirrhosis, and HCC (hepatocellular carcinoma). NAFLD is involved in reprogrammed hepatic metabolic machinery that lead to excessive lipid accumulation and imbalances in lipid metabolism and lipid catabolism in the liver. Hepatic lipid homeostasis is well described as a complex machinery including signaling and transcriptional pathways and targeted genes associated with fatty acid (FA) oxidation and lipogenesis. Although the pathogenesis of NAFLD have been widely studied for years, the molecular mechanisms underlying its complicated disorder is still investigated. Understanding of its pathogenesis and set new therapeutic strategies will be required to overcome the incidence of NAFLD in the worldwide. First, nuclear receptors (NRs), a superfamily of ligand-activated transcription factors, which regulated various biological homeostasis. Recently, the growing evidence provides NRs are key regulators in the progress of diverse hepatic diseases including glucose and lipid metabolism, inflammation, bile acid homeostasis, fibrosis, inflammation and cancer development in the liver. Thus, NRs are suggested as the promising therapeutic targets for diagnosis and treatment of NAFLD. Although nuclear receptors (NRs) play a crucial role in hepatic lipid metabolism, the underlying mechanisms of NR regulation in NAFLD remain largely unclear. Here, we revealed that MIR20B specifically targets PPARA through miRNA regulatory network analysis of nuclear receptor genes in NAFLD. The expression of MIR20B was upregulated in free fatty acid (FA)-treated hepatocytes and the livers of both obesity-induced mice and NAFLD patients. Overexpression of MIR20B significantly increased hepatic lipid accumulation and triglyceride levels. Furthermore, MIR20B significantly reduced FA oxidation and mitochondrial biogenesis by targeting PPARA. In Mir20b-introduced mice, the effect of fenofibrate to ameliorate hepatic steatosis was significantly suppressed. Finally, inhibition of Mir20b significantly increased FA oxidation and uptake, resulting in improved insulin sensitivity and a decrease in NAFLD progression. Moreover, combination of fenofibrate and anti-Mir20b exhibited the synergic effect on improvement of NAFLD in MCD-fed mice. Taken together, our results demonstrate that the novel MIR20B targets PPARA, plays a significant role in hepatic lipid metabolism, and present an opportunity for the development of novel therapeutics for NAFLD. Autophagy functions in cellular quality control and metabolic regulation. Dysregulation of autophagy is one of the major pathogenic factors contributing to the progression of non-alcoholic fatty liver disease (NAFLD). Autophagy is involved in the breakdown of intracellular lipids and the maintenance of healthy mitochondria in NAFLD. However, the mechanisms underlying autophagy dysregulation in NAFLD remain unclear. Here, we demonstrate that the hepatic expression of Thrap3 was increased in patients with NAFLD with the progression of fatty changes during NAFLD pathogenesis. Liver-specific Thrap3 knockout improved lipid accumulation and metabolic properties in high-fat diet (HFD)-induced NAFLD model. Further, Thrap3 deficiency enhanced autophagy and mitochondrial function. Interestingly, Thrap3 knockout increased the cytosolic translocation of AMPK from the nucleus and enhanced its activation through physical interaction. Our results indicate a role for Thrap3 in NAFLD progression and suggest that Thrap3 is a potential target for NAFLD treatment.