Lipid droplets (LDs) are a conserved feature of most organisms. Vertebrate adipocytes have evolved to efficiently store and release lipids for the whole organism from a single droplet. Perilipin 1, the most abundant lipid-coat protein in adipocytes, plays a key role in regulating lipolysis. In other tissues such as liver and muscle, LDs serve very different biological functions, buffering surplus lipids for subsequent oxidation or export. These tissues express perilipins 2 or 3, rather than perilipin 1. We sought to understand the role of perilipins 2 and 3 in regulating basal lipolysis. Bimolecular fluorescence complementation studies suggested that whereas perilipin 1 prevents the activation of adipose tissue triacylglycerol lipase by its coactivator, AB-hydrolase domain containing-5 (ABHD5), perilipins 2 and 3 do so less effectively. These differences are mediated by a conserved region within the carboxy terminus of perilipin 1 that binds and stabilizes ABHD5 by retarding its degradation by the proteosome. Chimeric proteins generated by fusing the carboxy terminus of perilipin 1 to the amino terminus of perilipins 2 or 3 stabilize ABHD5 and suppress basal lipolysis more effectively than WT perilipins 2 or 3. Furthermore, knockdown of perilipin 1 in adipocytes leads to replacement of perilipin 2 on LDs. In these cells we observed reduced ABHD5 expression and LD localization and a corresponding increase in basal lipolysis. Collectively these data suggest that whereas perilipin 1 potently suppresses basal lipolysis in adipocytes, perilipins 2 and 3 facilitate higher rates of basal lipolysis in other tissues where constitutive traffic of fatty acids via LDs is a necessary step in their metabolism.

Perilipin-1 is a lipid droplet coat protein predominantly expressed in adipocytes, where it inhibits basal and facilitates stimulated lipolysis. Loss-of-function mutations in PLIN1 were recently reported in patients with a novel subtype of familial partial lipodystrophy, designated as FPLD4. We now report the identification and characterization of a novel heterozygous frameshift mutation affecting the carboxy-terminus (439fs) of perilipin-1 in two unrelated families. The mutation co-segregated with a similar phenotype including partial lipodystrophy, severe insulin resistance and type 2 diabetes, extreme hypertriglyceridaemia and non-alcoholic fatty liver disease in both families. Poor metabolic control despite maximal medical therapy prompted two patients to undergo bariatric surgery, with remarkably beneficial consequences. Functional studies indicated that expression levels of the mutant protein were lower than wild type protein and in stably tranfected pre-adipocytes the mutant protein was associated with smaller lipid droplets. Interestingly, unlike the previously reported 398 and 404 frameshift mutants, this variant binds and stabilizes ABHD5 expression, but still fails to inhibit basal lipolysis as effectively as wild type perilipin-1. Collectively, these findings highlight the physiological need for exquisite regulation of neutral lipid storage within adipocyte lipid droplets, as well as the possible metabolic benefits of bariatric surgery in this serious disease.

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.