Abstract
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% α-tocopherol (α-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial β-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although α-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis.ConclusionL-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial β-oxidation and redox system.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease that is characterized by hepatic steatosis
Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD that is characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC) [1]
Body weight and biochemical analysis There were no significant differences in body weight among the three groups (Fig. 1A)
Summary
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease that is characterized by hepatic steatosis. Most patients with NAFLD exhibit non-progressive simple fatty liver, namely non-alcoholic fatty liver. Non-alcoholic steatohepatitis (NASH) is a more severe form of NAFLD that is characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC) [1]. These features were defined by Ludwig et al in 1980 to describe a liver disease that histologically mimics alcoholic hepatitis but occurs in individuals who do not abuse alcohol [2]. Ultrastructural alterations, impairment of adenosine triphosphate synthesis, and increased production of ROS have been reported in liver mitochondria from NASH patients and a rodent model [4,5]
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