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

Abstract

Background & Aims\n\nHepatosteatosis, defined as excessive intrahepatic lipid accumulation,\nrepresents the first step of NAFLD. When combined with additional cellular\nstress, this benign status progresses to local and systemic pathological\nconditions such as NASH and\ninsulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in\nterms of its impact on liver biology and other peripheral organs, remain\nunclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme\nfor long chain fatty acid beta-oxidation in the liver.\nHere we utilise hepatocyte-specific Cpt1a\nknockout (LKO) mice to investigate the physiological consequences of abolishing\nhepatic long chain fatty acid metabolism.\n\nApproach &\nResults \n\nCompared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were\notherwise protected against diet-induced\nweight gain, insulin resistance, hepatic ER stress, inflammation and damage.\nInterestingly, increased energy expenditure was observed in LKO mice, accompanied\nby enhanced adipose tissue browning. RNAseq analysis\nrevealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast\ngrowth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly,\nantibody-mediated neutralization of FGF21 abolished the\nhealthier metabolic phenotype and adipose browning in LKO\nmice, indicating that the elevation of FGF21 contributes to the\nimproved liver pathology and adipose browning in HFD-treated LKO mice. \n\nConclusions\n\nLiver with deficient CPT1A\nexpression 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.