Hepatocyte-specific PKC beta 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 (PKC 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 PKC beta in energy homeostasis is limited. Methods: The floxed-PKC beta and hepatocyte-specific PKC beta-deficient mouse models were generated to study the in vivo role of hepatocyte PKC beta on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function. Results: We report that hepatocyte-specific PKC beta 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 PKC beta-deficient livers compared to control. Moreover, hepatocyte PKC beta 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 PKC beta 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 PKC beta as a drug target for obesity-associated nonalcoholic hepatic steatosis. (C) 2020 The Authors. Published by Elsevier GmbH.

Automated summary

Protein kinase C beta (PKC beta) plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli, particularly in the development of hepatic steatosis induced by high-fat diet. The hepatocyte-specific PKC beta deficiency offers protection against hepatic steatosis without affecting insulin sensitivity.