Abstract
Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization.
Highlights
Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family
PLIN5 ablation had no effect on body weight or liver weight during the 3 week treatment period (Fig. 1B, C); PLIN5 antisense oligonucleotide (ASO) mildly reduced adipose PLIN5 expression, but no changes in weight of the various adipose depots were observed
Overnight fasting increased hepatic LD accumulation and TAG content compared with refeeding as expected, and PLIN5 ASO-treated mice had reduced abundance of hepatic LDs and TAG content in both fasted and refed conditions (Fig. 1D–F)
Summary
Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Following PKA-mediated phosphorylation, PLIN5 translocates to the nucleus where it interacts with and promotes the activity of SIRT1 and the transcriptional complex of PGC1- /PPAR- to increase the expression of downstream target genes governing mitochondrial biogenesis and oxidative metabolism [10]. This increase in mitochondrial number and function may be a key factor in uncoupling LD accumulation from insulin resistance and cellular dysfunction. We report that PLIN5 promotes fasting-induced autophagy and prevents FA-induced inflammation as a means to uncouple LD accumulation from metabolic dysfunction
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