Elsevier

Molecular Metabolism

Volume 44, February 2021, 101133
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2020.101133Get rights and content
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open access

Highlights

  • Hepatocyte-specific PKCβ deficiency protects from diet-induced hepatic steatosis but not either obesity or insulin resistance.

  • The underlying mechanism involves modulation of mitochondrial function and lipogenesis.

  • Hepatocyte PKCβ does not regulate hepatic insulin signaling.

  • Our study provides a link between dietary lipid intake, hepatic protein kinase Cβ, modulation of hepatic lipid metabolism, and development of hepatic steatosis.

Abstract

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 (PKCβ), 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 PKCβ in energy homeostasis is limited.

Methods

The floxed-PKCβ and hepatocyte-specific PKCβ-deficient mouse models were generated to study the in vivo role of hepatocyte PKCβ on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function.

Results

We report that hepatocyte-specific PKCβ 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 PKCβ-deficient livers compared to control. Moreover, hepatocyte PKCβ 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 PKCβ 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 PKCβ as a drug target for obesity-associated nonalcoholic hepatic steatosis.

Keywords

Dietary fats
Protein kinase cβ
Hepatic steatosis
Mitochondria respiratory chain

Abbreviations

AKT
protein kinase B
FCCP
trifluoromethoxy carbonyl cyanide phenylhydrazine
HFD
high-fat diet
IRS
insulin receptor substrate
MEK
mitogen-extracellular kinase
mTOR
mechanistic target of rapamycin
OCR
oxygen consumption rate
PKCβ
protein kinase Cβ
PKCβfl/fl
floxed PKCβ mice
PKCβHep−/−
hepatocyte-specific PKCβ-deficient mice
SREBP-1c
sterol response element-binding protein-1c
TG
triglycerides
VLDL
very low-density lipoproteins
WAT
adipose tissue

Cited by (0)

7

Yaoling Shu and Faizule Hassan contributed equally to this work.