Hepatocyte-secreted Autotaxin Exacerbates Nonalcoholic Fatty Liver Disease Through Autocrine Inhibition of the PPARalpha/FGF21 axis.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally due to the rapid rise in obesity. However, there is no FDA-approved pharmacotherapy available for NAFLD. This study aims to investigate the role of autotaxin (ATX), a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacological interventions targeting autotaxin ameliorate NAFLD.

METHODS: Clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or FGF21-null mice were fed with high-fat diet or choline-deficient diet to interrogate the roles of autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.

RESULTS: Serum autotaxin levels were positively associated with histological scores and severity of NAFLD. Hepatocytes but not adipocytes were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced non-alcoholic steatohepatitis (NASH) and fibrosis, accompanied by a marked elevation of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of PPARα through LPA-induced activation of ERK, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.

CONCLUSIONS: Liver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the PPARα-FGF21 axis and is a promising therapeutic target for NAFLD.