<b>Background & Aims</b>
<p>Hepatosteatosis, defined as excessive intrahepatic lipid accumulation,
represents the first step of NAFLD. When combined with additional cellular
stress, this benign status progresses to local and systemic pathological
conditions such as NASH and
insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in
terms of its impact on liver biology and other peripheral organs, remain
unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme
for long chain fatty acid beta-oxidation in the liver.
Here we utilise hepatocyte-specific <i>Cpt1a</i>
knockout (LKO) mice to investigate the physiological consequences of abolishing
hepatic long chain fatty acid metabolism.</p>
<p><b>Approach &
Results </b></p>
<p>Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were
otherwise protected against diet-induced
weight gain, insulin resistance, hepatic ER stress, inflammation and damage.
Interestingly, increased energy expenditure was observed in LKO mice, accompanied
by enhanced adipose tissue browning. RNAseq analysis
revealed that the peroxisome proliferator activator alpha (PPARα)- 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. </p>
<p><b>Conclusions</b></p>
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.