Transcriptional response to fasting studied in the liver of mice that express phosphorylation resistant perilipin 5

Perilipin 5 (PLIN5) is a lipid droplet protein highly expressed in cells that actively oxidize fatty acids. Previous in vitro studies have revealed that PLIN5 phosphorylation (p-PLIN5) at serine 155 by PKA is critical for transcriptional regulation of PPARa target genes by which PLIN5 adapt cells for fatty acid oxidation. We aim to determine the extent of p-PLIN5 in vivo and the consequence of impaired PLIN5 phosphorylation in the liver by using a whole-body knock-in of phosphorylation resistant PLIN5 (SA/SA) in mice.

Plin5 phosphorylation at S155 was increased in the liver LD fraction of fasted mice compared with that of fed mice by mass spectrometry (p<0.05). qPCR of key lipid metabolism genes did not differ between WT and SA/SA liver upon fasting in both young and old males. Young SA/SA female mice showed a small but significant reduction in the expression of Ppara and Cpt1a genes in the liver after overnight fasting. Male SA/SA mice had a higher fasting blood glucose (p<0.05) without a difference in body weight, serum insulin, or serum lipids. IRS2 was reduced in the liver of fasted male SA/SA mice (p<0.05).

PLIN5 S155 phosphorylation has a limited impact on the upregulation of hepatic lipid metabolism genes important for fasting response in vivo in females and is largely dispensable in males. Impaired phosphorylation also had little effect on serum lipids or liver TG. However, old SA/SA mice showed decreased IRS2 expression in the liver, which may contribute to glucose intolerance in SA/SA male mice.