Abstract
We showed previously that UBXD8 plays a key role in proteasomal degradation of lipidated ApoB in hepatocarcinoma cell lines. In the present study, we aimed to investigate the functions of UBXD8 in liver in vivo. For this purpose, hepatocyte-specific UBXD8 knockout (UBXD8-LKO) mice were generated. They were fed with a normal or high-fat diet, and the phenotypes were compared with those of littermate control mice. Hepatocytes obtained from UBXD8-LKO and control mice were analyzed in culture. After 26 wk of a high-fat diet, UBXD8-LKO mice exhibited macrovesicular steatosis in the periportal area and microvesicular steatosis in the perivenular area, whereas control mice exhibited steatosis only in the perivenular area. Furthermore, UBXD8-LKO mice on a high-fat diet had significantly lower concentrations of serum triglyceride and VLDL than control mice. A Triton WR-1339 injection study revealed that VLDL secretion from hepatocytes was reduced in UBXD8-LKO mice. The decrease of ApoB secretion upon UBXD8 depletion was recapitulated in cultured primary hepatocytes. Accumulation of lipidated ApoB in lipid droplets was observed only in UBXD8-null hepatocytes. The results showed that depletion of UBXD8 in hepatocytes suppresses VLDL secretion, and could lead to periportal steatosis when mice are fed a high-fat diet. This is the first demonstration that an abnormality in the intracellular ApoB degradation mechanism can cause steatosis, and provides a useful model for periportal steatosis, which occurs in several human diseases.
Highlights
Steatosis is highly prevalent in Western countries and may lead to steatohepatitis, cirrhosis, and liver cancer [1,2]
Hepatocyte-specific UBXD8-deficient mice had significantly lower levels of serum very low-density lipoproteins (VLDL) and TG than control mice. These results indicated that deficiency of UBXD8 in hepatocytes compromises lipid droplets (LDs) functionality, decreases VLDL secretion, and predisposes to steatosis
Considering that TG and cholesterol are largely present in the core and the outer phospholipid monolayer of the VLDL particle, respectively, these results suggested that lipidation of apolipoprotein B (ApoB) is defective in the UBXD8-null hepatocytes
Summary
Steatosis (fatty liver) is highly prevalent in Western countries and may lead to steatohepatitis, cirrhosis, and liver cancer [1,2]. Manipulated mouse models have shown that defects in lipid metabolism are conductive to steatosis and/or steatohepatitis [5]. Hepatocytes in steatotic liver harbor a large number of lipid droplets (LDs) in the cytoplasm. The LD is an organelle that exists in many types of cells and stores lipid esters, mainly triglycerides (TG) and cholesterol esters, which are mobilized for various physiological processes such as β-oxidation and membrane biogenesis [6,7]. The excess LDs in steatotic liver indicate some abnormality that could be related to overproduction of lipid esters or a deficiency in lipid ester hydrolysis and use
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