Abstract
In this study, we explored the effects of Bax Inhibitor-1 (BI-1) on ApoB aggregation in high-fat diet (HFD)-induced hepatic lipid accumulation. After 1 week on a HFD, triglycerides and cholesterol accumulated more in the liver and were not effectively secreted into the plasma, whereas after 8 weeks, lipids were highly accumulated in both the liver and plasma, with a greater effect in BI-1 KO mice compared with BI-1 WT mice. ApoB, a lipid transfer protein, was accumulated to a greater extent in the livers of HFD-BI-1 KO mice compared with HFD-BI-1 WT mice. Excessive post-translational oxidation of protein disulfide isomerase (PDI), intra-ER ROS accumulation and folding capacitance alteration were also observed in HFD-BI-1 KO mice. Higher levels of endoplasmic reticulum (ER) stress were consistently observed in KO mice compared with the WT mice. Adenovirus-mediated hepatic expression of BI-1 in the BI-1 KO mice rescued the above phenotypes. Our results suggest that BI-1-mediated enhancement of ApoB secretion regulates hepatic lipid accumulation, likely through regulation of ER stress and ROS accumulation.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver in the absence of ‘significant’ alcohol consumption, and can progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma[1]
Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels were markedly elevated both in Bax inhibitor-1 (BI-1) wild type (WT) and KO mice after 8 weeks on a high-fat diet (HFD), and ALT and AST levels were more significantly increased in KO than WT mice (Supplementary Fig. 1a)
Increased levels of serum ALT and AST in HFD-BI-1 KO mice were significantly reduced by infection with adenovirus BI-1 in contrast to infection with the adenovirus GFP control (Supplementary Fig. 1b)
Summary
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver in the absence of ‘significant’ alcohol consumption, and can progress to nonalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma[1]. When pathological ER stress conditions are not regulated by the adaptive response, the physiological degradation machinery does not function efficiently, leading to the accumulation of unfolded proteins, including ApoB7. During this type of ER stress, hepatic lipid synthesis and secretion may be affected by alterations in the folding process of secretory ApoB proteins[8]. Its cytoprotective function is well-conserved in plants and mammals[10,11] Based upon these observations, we examined the potential regulatory effects of BI-1 on hepatic dyslipidemia. Our results suggest a regulatory mechanism of BI-1 in hepatic dyslipidemia
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