Hepatocyte-specific depletion of ubiquitin regulatory X domain containing protein 8 accelerates fibrosis in a mouse non-alcoholic steatohepatitis model

Ubiquitin regulatory X domain-containing protein 8 (UBXD8) is engaged in the degradation of lipidated apolipoprotein B in hepatocytes. We previously showed that hepatocyte-specific UBXD8-deficient mice (U8-HKO) fed a moderately high-fat diet (31 kcal % fat) showed periportal macrovesicular steatosis along with a decrease in very low-density lipoprotein secretion, but did not develop fibrosis. In the present study, we examined whether U8-HKO mice show NASH-like phenotypes when fed a very high-fat diet (60 kcal % fat). U8-HKO mice and their age-matched littermates (control) were fed with two NASH model diets: choline-sufficient very high-fat diet and choline-deficient very high-fat diet. After being fed a very high-fat diet for 2 weeks, U8-HKO mice showed hepatic fibrosis in a significantly wider area than in the control. Fibrosis in U8-HKO mouse liver was further enhanced under a very high-fat diet depleted of choline (the liver surface was lumpy). Concomitant administration of an angiotensin 2 type 1 receptor blocker reduced the hepatic fibrosis caused by the very high-fat diet, suggesting the existence of inflammation. Carbon tetrachloride also induced hepatic fibrosis but the severity was comparable in the control and U8-HKO mice. In conjunction with our previous finding, the results indicate that although UBXD8 functionality can be largely compensated in the normal setting, it is crucial to sustain VLDL secretion when exposed to a dietary challenge of high fat. U8-HKO mice that develop fibrosis within 2 weeks of high-fat feeding can be used as a model to study NAFLD/NASH disease progression.