MicroRNAs in the Pathogenesis of Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), or, more accurately, metabolic associated fatty liver disease, accounts for a large proportion of chronic liver disorders worldwide and is closely associated with other conditions such as cardiovascular disease, obesity, and type 2 diabetes mellitus. NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and can progress to cirrhosis and, eventually, also hepatocellular carcinoma. The morbidity and mortality associated with NAFLD are increasing rapidly year on year. Consequently, there is an urgent need to understand the etiology and pathogenesis of NAFLD and identify effective therapeutic targets. MicroRNAs (miRNAs), important epigenetic factors, have recently been proposed to participate in NAFLD pathogenesis. Here, we review the roles of miRNAs in lipid metabolism, inflammation, apoptosis, fibrosis, hepatic stellate cell activation, insulin resistance, and oxidative stress, key factors that contribute to the occurrence and progression of NAFLD. Additionally, we summarize the role of miRNA-enriched extracellular vesicles in NAFLD. These miRNAs may comprise suitable therapeutic targets for the treatment of this condition.

Keywords: NAFLD; Nonalcoholic fatty liver disease; Pathogenesis; miRNAs.

Figure 1

The role of miRNA-enriched extracellular vesicles (EVs) in intercellular communication in nonalcoholic fatty liver disease (NAFLD). Adipose tissue-derived macrophages secrete miR-155-enriched EVs, which are internalized by hepatocytes and impair insulin sensitivity. MiR-223-enriched EVs released by neutrophils and macrophages are absorbed by hepatocytes and improve hepatic inflammation and fibrosis. MiR-214-containing EVs encapsulated by hepatic stellate cells (HSCs) can simultaneously be absorbed by HSCs and hepatocytes and decrease the expression of fibrogenesis-related genes by suppressing CCN2. Hepatocytes also secrete miR-192-5p-enriched EVs, which are internalized by macrophages, where they promote inflammation and induce M1 polarization. Hepatocytes also release miR-1-enriched EVs, which are transferred to endothelial cells to promote inflammation by targeting KLF4. Moreover, miR-128-3p-containing EVs released by hepatocytes can be taken up by HSCs and increase HSC activation by inhibiting PPARγ.

Figure 2

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Dietary factors and obesity, important for the development of insulin resistance, increase the lipolysis of adipose tissue and de novo lipogenesis (DNL) in hepatocytes. An excess of free fatty acids from circulating blood enters the liver, which, together with increased DNL in hepatocytes, leads to hepatocyte steatosis and lipotoxicity. The latter can affect the normal functioning of mitochondria and endoplasmic reticulum, leading to oxidative stress and endoplasmic reticulum stress, which can increase hepatocyte apoptosis. Apoptotic hepatocytes increase the production of proinflammatory cytokines, recruit inflammatory cells to the liver, activate Kupfer cells, and lead to inflammation, which is a hallmark of NASH. At the same time, inflammation and hepatocyte apoptosis promote the activation of hepatic stellate cells (HSCs), which will transform into myofibroblasts and produce extracellular matrix. Excessive deposition of extracellular matrix leads to the occurrence of liver fibrosis.