Abstract
Nonalcoholic fatty liver disease (NAFLD) consists of the entire spectrum of fatty liver disease in patients without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to cirrhosis, with NASH recently shown as an important cause of hepatocellular carcinoma (HCC). There is a close relationship between insulin resistance (IR) and NAFLD, with a five-fold higher prevalence of NAFLD in patients with type 2 diabetes (T2DM) compared to that in patients without T2DM. IR is involved in the progression of disease conditions such as steatosis and NASH, as well as hepatic fibrosis progression. The mechanisms underlying these processes involve genetic factors, hepatic fat accumulation, alterations in energy metabolism, and inflammatory signals derived from various cell types including immune cells. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell (HSC). HSC activation by IR involves “direct” and “indirect” pathways. This review will describe the molecular mechanisms of inflammation and hepatic fibrosis in IR, the relationship between T2DM and hepatic fibrosis, and the relationship between T2DM and HCC in patients with NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a major form of chronic liver disease that affects both adults and children worldwide [1]. It is one of the clinical consequences of obesity and can progress to nonalcoholic steatohepatitis (NASH), which is pathologically characterized by the presence of steatosis, inflammation, and fibrosis in the liver parenchyma, which leads to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure [1,2,3]
High mobility group box 1 (HMGB1) is released by injured hepatocytes to nonalcoholic steatohepatitis (NASH) but not simple steatosis directly leads to hepatic stellate cell (HSC) activation through the release of Indian hedgehog (Ihh) and promotes hepatocyte injury and inflammation that may indirectly promote HSC activation
We reported that homeostasis model assessment parameter (HOMA)-insulin resistance (IR) ≥ 2.90 was an independent predictor of advanced fibrosis in nondiabetic NAFLD patients, and our data suggest that there may be a pathway for IR to directly activate HSCs [99]
Summary
Nonalcoholic fatty liver disease (NAFLD) is a major form of chronic liver disease that affects both adults and children worldwide [1] It is one of the clinical consequences of obesity and can progress to nonalcoholic steatohepatitis (NASH), which is pathologically characterized by the presence of steatosis, inflammation, and fibrosis in the liver parenchyma, which leads to cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver failure [1,2,3]. As described later, improving IR can be one of the potential therapeutic approaches for NASH fibrosis, even in the absence of T2DM This is an innovative review because we discussed the influence of IR on the progression of hepatic fibrosis in NAFLD, both in basic and clinical aspects, for the first time. Some of the studies reported in this review analyzed data from the Japan Study Group of NAFLD (JSG-NAFLD)
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