Human Congenital Perilipin Deficiency and Insulin Resistance

Abstract

Lipid droplets (LDs) can form in all eukaryotic cells, but white adipocytes are uniquely adapted to store energy as neutral lipid within a large unilocular LD. Non-esterified fatty acids can then be released from the LD store by lipases for use in oxidative tissues. Perilipin was the first mammalian LD protein to be identified in adipocytes where it plays a key role in co-ordinating access of lipases to the core triacylglycerol. We recently identified the first human loss-of-function mutations in PLIN1 in patients with a novel form of familial partial lipodystrophy, severe insulin resistance, diabetes, dyslipidaemia and fatty liver. Adipose tissue samples from affected patients revealed remarkably similar features to those previously observed in samples from obese insulin resistant patients, namely macrophage infiltration and fibrosis. Cellular mechanistic studies suggest that the mutations lead to increased basal lipolysis, which is likely to be a major factor in the subsequent inflammatory response. Perilipin is almost exclusively expressed in white adipocytes, so the serious metabolic sequelae observed in these patients suggest that primary defects in adipose tissue can lead to all the typical features seen in patients with the metabolic syndrome. They also suggest that lipolytic inhibitors may be therapeutically useful in these patients.

Omega-3 polyunsaturated fatty acids attenuate inflammatory activation and alter differentiation in human adipocytes

“…This delicate balance between lipid storage and release may underlie the often contradictory data surrounding association of lipid storage genes expression with metabolic health. On one hand, human studies have shown that increased expression of lipogenic genes CIDE and perilipin in adipose were correlated with lower BMI and higher insulin sensitivity, and humans with perilipin deficiency have severe insulin resistance [54]. On the contrary, both CIDEC and perilipin1 knockout mice were protected against obesity and insulin resistance [55], underscoring the importance of human models in understanding lipid physiology.…”

Genetic Disorders of Insulin Action: Far More than Diabetes

“…Mutations causing autosomal dominant FPLD lead to a relative diminution of subcutaneous adipose tissue on the limbs, though this may sometimes be subtle, with severe dyslipidemia and often early onset hypertension [48]. A handful of rarer mutations have also been described, including defects in two different lipid droplet proteins, perilipin [49] and CIDEC [50], which play distinct roles in the mobilization of triglyceride stores from the single large lipid droplet in fat cells. Deficiency of CIDEC in a single patient has been shown to give rise to a unique multilocular appearance of residual white adipose tissue, quite unlike the usual single large lipid droplet normally seen [50].…”

Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis

“…PLIN2-KO mice are also protected against diet induced obesity, fatty liver and inflammation presumably via increased browning and decreased food intake (McManaman JL, 2013). On the other hand, PLIN1 loss of function mutation causes increased basal lipolysis, lipodystrophy and insulin resistance in humans (Kozusko K, 2013) which is explainable as the balance between lipolysis and energy expenditure is disturbed which is important to maintain insulin sensitivity. Thus, targeting PLIN1 and energy expenditure is beneficial in obesity and diabetes.…”