Perilipin Deficiency and Autosomal Dominant Partial Lipodystrophy

Abstract

Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.

Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease

“…We have recently reported the fact that loss-of-function mutations in two of these LD coat proteins are associated with smaller LDs and lipodystrophy (19,20). We have now also shown that siRNA-mediated PCYT1A knockdown impairs adipogenesis in cultured adipocytes.…”

Perilipins 2 and 3 lack a carboxy-terminal domain present in perilipin 1 involved in sequestering ABHD5 and suppressing basal lipolysis

“…In adipocytes, lipolytic regulation affects free fatty acid delivery to all other tissues in the whole organism, whereas most other tissues largely regulate lipid stores in a cell-autonomous fashion, an obvious exception being hepatocytes, which can release TAG within lipoproteins. The fact that patients with loss-of-function mutations in perilipin 1, shown to result in elevated basal lipolysis, manifest such severe metabolic consequences including partial lipodystrophy, severe insulin resistance, diabetes, dyslipidaemia, and nonalcoholic fatty liver disease highlights the importance of perilipin 1 in regulating adipocyte lipolysis (22,23). In the fasting state or during exercise, lipolysis is dramatically increased (severalfold) to deliver free fatty acids for oxidative phosphorylation in muscle and other energetically demanding tissues.…”

“…Granneman et al (21) later showed that this interaction sequestered ABHD5 from interacting with ATGL whereas they suggested that the interaction between perilipin 2 and ABHD5 was significantly weaker (21). We recently identified lossof-function frameshift PLIN1 mutations in patients with partial lipodystrophy, severe insulin resistance, dyslipidaemia, and nonalcoholic fatty liver disease (22). When expressed in cultured adipocytes, the mutants, which primarily alter the C terminus of perilipin 1, failed to sequester ABHD5 from ATGL or to suppress basal lipolysis (23).…”

Clinical Utility Gene Card for: Familial partial lipodystrophy

“…Two deletions and one splice site variant, all resulting in frameshifts, have been identified. 10,11 Two of them have been shown to alter physiological functions of perilipin. 12 CIDEC-FPLD5 is an autosomal recessive disorder.…”