Hepatocyte-specific PKCβ deficiency protects against high-fat diet-induced nonalcoholic hepatic steatosis.

OBJECTIVE:Nonalcoholic hepatic steatosis, also known as fatty liver, is a uniform response of the liver to hyperlipidic-hypercaloric diet intake. However, the post-ingestive signals and mechanistic processes driving hepatic steatosis are not well understood. Emerging data demonstrate that protein kinase C beta a lipid-sensitive kinase, plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli. Despite its powerful effect on glucose and lipid metabolism, knowledge of the physiological roles of hepatic in energy homeostasis is limited. METHODS:The and hepatocyte-specific mouse models were generated to study the in vivo role of hepatocyte duanyu1531β on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function. RESULTS:We report that hepatocyte-specific duanyu1531β deficiency protects mice from development of hepatic steatosis induced by high-fat diet, without affecting body weight gain. This protection is associated with attenuation of SREBP-1c transactivation and improved hepatic mitochondrial respiratory chain. Lipidomic analysis identified significant increases in the critical mitochondrial inner membrane lipid, cardiolipin, in duanyu1531β-deficient livers compared to control. Moreover, hepatocyte duanyu1531β deficiency had no significant effect on either hepatic or whole-body insulin sensitivity supporting dissociation between hepatic steatosis and insulin resistance. CONCLUSIONS:The above data indicate that hepatocyte duanyu1531β is a key focus of dietary lipid perception and is essential for efficient storage of dietary lipids in liver largely through coordinating energy utilization and lipogenesis during post-prandial period. These results highlight the importance of hepatic duanyu1531β as a drug target for obesity-associated nonalcoholic hepatic steatosis.

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