Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH)

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non-alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression of NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, which in turn induces hepatic steatosis, inflammation and fibrosis. Among these factors, gut microbiota are acknowledged as having an important role in initiating this multifactorial disease. Oxidative stress is considered to be a key contributor in the progression from NAFL to NASH. Macrophage infiltration is apparent in NAFL and NASH, while T-cell infiltration is apparent in NASH. Although several clinical trials have shown that antioxidative therapy with vitamin E can effectively control hepatitis pathology in the short term, the long-term effects remain obscure and have often proved to be ineffective in many other diseases. Several long-term antioxidant protocols have failed to reduce mortality. New treatment modalities that incorporate current understanding of NAFLD molecular pathogenesis must be considered.

Figure 1.

Histological findings of NAFLD. Liver biopsy specimens of NAFLD patients are shown. Representative findings of four classifications are shown, as reported by Matteoni et al. in 1999 [2]. Type 1: steatosis alone (×100, Hematoxylin and eosin (H and E) staining); Type 2: steatosis with lobular inflammation (×100, H and E staining); Type 3: steatosis with hepatocyte ballooning (×200, H and E staining) and Mallory-Denk body; Type 4: type 3 plus either Mallory-Denk bodies or fibrosis (×40, Azan staining). Scale bar: 50 μm.

Figure 2.

Multiple hits in NAFL and NASH. (A) Multiple hits in NAFL are shown. Genome-wide association studies have confirmed the importance of the patatin-like phospholipase 3 (PNPLA3) gene polymorphism in NAFLD. This genetic polymorphism is able to differentiate simple steatosis with or without minimal inflammation and fibrosis progressing to NASH. The gut microbiome has recently been recognized as being involved in NAFLD development. The pattern of microbiome diversity can induce intestinal mucosal permeability and result in lipopolysaccharidemia, which correlates with NASH progression. Enteric bacteria suppress the synthesis of fasting-induced adipocyte factor (Fiaf) resulting in increased lipoprotein lipase (LPL) activity and increased triglyceride accumulation. Obesity and diabetes induce insulin resistance, adipocyte proliferation and changes in intestinal flora. Macrophages play an important role in the induction of inflammation and insulin resistance; (B) Ingestion of free fatty acids and free cholesterol induce ER stress and oxidative stress, resulting in hepatic inflammation and fibrogenesis that induces progression to NASH. In some instances, inflammation could precede steatosis, and antitumor necrosis factor (TNF)-α antibody improves steatosis in ob/ob mice. CD4(+)T cells are found after NASH development. Adipokines such as IL-6 and TNF-α produced by adipocytes affect hepatocyte fat content and the liver inflammatory environment. Mallory-Denk bodies are large eosinophilic hepatocellular cytoplasmic protein aggregates containing CK (cytokeratin)-18, which is a hallmark of alcoholic hepatitis and NASH. Heading numbers are consistent with those used in the main text.

Figure 2.

Multiple hits in NAFL and NASH. (A) Multiple hits in NAFL are shown. Genome-wide association studies have confirmed the importance of the patatin-like phospholipase 3 (PNPLA3) gene polymorphism in NAFLD. This genetic polymorphism is able to differentiate simple steatosis with or without minimal inflammation and fibrosis progressing to NASH. The gut microbiome has recently been recognized as being involved in NAFLD development. The pattern of microbiome diversity can induce intestinal mucosal permeability and result in lipopolysaccharidemia, which correlates with NASH progression. Enteric bacteria suppress the synthesis of fasting-induced adipocyte factor (Fiaf) resulting in increased lipoprotein lipase (LPL) activity and increased triglyceride accumulation. Obesity and diabetes induce insulin resistance, adipocyte proliferation and changes in intestinal flora. Macrophages play an important role in the induction of inflammation and insulin resistance; (B) Ingestion of free fatty acids and free cholesterol induce ER stress and oxidative stress, resulting in hepatic inflammation and fibrogenesis that induces progression to NASH. In some instances, inflammation could precede steatosis, and antitumor necrosis factor (TNF)-α antibody improves steatosis in ob/ob mice. CD4(+)T cells are found after NASH development. Adipokines such as IL-6 and TNF-α produced by adipocytes affect hepatocyte fat content and the liver inflammatory environment. Mallory-Denk bodies are large eosinophilic hepatocellular cytoplasmic protein aggregates containing CK (cytokeratin)-18, which is a hallmark of alcoholic hepatitis and NASH. Heading numbers are consistent with those used in the main text.