Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function

Abstract

Dysfunctional cellular lipid metabolism contributes to common chronic human diseases, including type 2 diabetes, obesity, fatty liver disease and diabetic cardiomyopathy. How cells balance lipid storage and mitochondrial oxidative capacity is poorly understood. Here we identify the lipid droplet protein Perilipin 5 as a catecholamine-triggered interaction partner of PGC-1α. We report that during catecholamine-stimulated lipolysis, Perilipin 5 is phosphorylated by protein kinase A and forms transcriptional complexes with PGC-1α and SIRT1 in the nucleus. Perilipin 5 promotes PGC-1α co-activator function by disinhibiting SIRT1 deacetylase activity. We show by gain-and-loss of function studies in cells that nuclear Perilipin 5 promotes transcription of genes that mediate mitochondrial biogenesis and oxidative function. We propose that Perilipin 5 is an important molecular link that couples the coordinated catecholamine activation of the PKA pathway and of lipid droplet lipolysis with transcriptional regulation to promote efficient fatty acid catabolism and prevent mitochondrial dysfunction.

Lipid droplet functions beyond energy storage

“…An exciting recent finding is that in mice the LD protein PLIN5 can, under certain conditions, translocate from the droplet surface to the nucleoplasm and stimulate gene expression [165]. PLIN5 is a member of the Perilipin family of proteins, the most heavily studied family of LD proteins [17].…”

“…It controls lipolysis by regulating access of cytoplasmic lipases to the neutral lipids stored in LDs, and also mediates LD-mitochondrial interactions. In starved animals and in cells after stimulation of the protein kinase A (PKA) pathway, a substantial fraction of PLIN5 was found to relocalize to the nucleus [165]. Phosphorylation of PLIN5 by PKA drives relocalization and assembly into a protein complex with PGC-1α and SIRT-1.…”

“…PGC-1 α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional regulator important for mitochondrial biogenesis and function; SIRT-1 (Sirtuin 1) is a deacetylase that controls PGC-1 α's acetylation status and activity. PLIN5 mediates PKA-dependent activation of PGC-1α, presumably by disinhibiting SIRT-1, and thus activates PGC-1α target genes [165]. PLIN5 thus serves two functions in two different cellular locations: on LDs it regulates the activity of lipases and, in the nucleus it acts as a transcriptional activator.…”

Perilipin 5 and liver fatty acid binding protein function to restore quiescence in mouse hepatic stellate cells

“…Pin5 was reported to be phosphorylated by protein kinase A (PKA) (49)(50)(51), and the serine at 155 in Plin5 has been proposed as the PKA phosphorylation site (50). Phosphorylation of Pin5 by PKA stimulated the interaction of Plin5 and ATGL (51), which might play a critical role in Plin5-regulated lipolysis (50).…”

“…Phosphorylation of Pin5 by PKA stimulated the interaction of Plin5 and ATGL (51), which might play a critical role in Plin5-regulated lipolysis (50). Plin5 has been proposed to be an important molecular link that couples the coordinated catecholamine activation of the PKA pathway and of lipid droplet lipolysis with transcriptional regulation to promote efficient fatty acid catabolism (49). The possibility that Plin5 modulates lipid hydrolysis in HSCs and the role if any for L-Fabp will require further study.…”