Hepatic CPT1A Facilitates Liver Adipose Cross Talk via Induction of FGF21 in Mice

Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of nonalcoholic fatty liver disease (NAFLD). When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as nonalcoholic steatohepatitis and insulin resistance. However, the molecular events directly caused by hepatic lipid buildup, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for long-chain fatty acid beta-oxidation in the liver. In this study, we use hepatocyte-specific Cptla knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long-chain fatty acid metabolism. Compared with the wild-type littermates, high-fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic endoplasmic reticulum stress, inflammation, and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNA-sequencing analysis revealed that the peroxisome proliferator-activated receptor alpha-fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody- mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

Automated summary

This study reveals that deficiency of hepatic CPT1A protects against high-fat diet-induced liver damage and enhances adipose browning. Activation of the peroxisome proliferator-activated receptor alpha-fibroblast growth factor 21 (FGF21) axis in the liver contributes to the improved metabolic state.