Lipodystrophies: disorders of adipose tissue biology

Abstract

The adipocytes synthesize and store triglycerides as lipid droplets surrounded by various proteins and phospholipids at its surface. Recently, the molecular basis of some of the genetic syndromes of lipodystrophies has been elucidated and some of these genetic loci have been found to contribute to lipid droplet formation in adipocytes. The two main types of genetic lipodystrophies are congenital generalized lipodystrophy (CGL) and familial partial lipodystrophy (FPL). So far, three CGL loci: 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1) and four FPL loci: lamin A/C (LMNA), peroxisome proliferator-activated receptor gamma (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24), have been identified. AGPAT2 plays a critical role in the synthesis of glycerophospholipids and triglycerides required for lipid droplet formation. Another protein, seipin (encoded by BSCL2 gene), has been found to induce lipid droplet fusion. CAV1 is an integral component of caveolae and might contribute towards lipid droplet formation. PPARgamma and AKT2 play important role in adipogenesis and lipid synthesis. In this review, we discuss and speculate about the contribution of various lipodystrophy genes and their products in the lipid droplet formation.

Fig. 1. Phenotypes of Congenital generalized lipodystrophy and familial partial lipodystrophy of the Dunnigan variety

A. and B. Front and lateral views of a 19-year-old female of African-American origin with congenital generalized lipodystrophy, type 1 due to 1-acylglycerol-3-phosphate acyltransferase 2 (AGPAT2) homozygous mutation. She has generalized lack of body fat, marked muscularity, acanthosis nigricans in the neck and axillae and acromegaloid features and umbilical prominence. She developed diabetes at the age of 14 years and severe hypertriglyceridemia was noted 15 years of age. C and D. Front and lateral views of a 24-year-old Hispanic woman with familial partial lipodystrophy of the Dunnigan variety due to heterozygous missense mutation in the Lamin A/C (LMNA) gene. She had fat loss the upper and lower extremities and trunk at puberty and also accumulated excess fat in the face, submental, supraclavicular and vulvar regions. She had mild acanthosis nigricans in the neck and axillae.

Fig. 2. The triglyceride and glycerophospholipid biosynthetic pathway in the adipose tissue

Adipose tissue requires glycerol-3-phosphate as the initial substrate for triglyceride and glycerophospholipid biosynthesis. Initially, glycerol-3-phosphate is acylated using fatty acyl coenzyme A (FA-CoA) at the sn-1 position by the class of enzymes called glycerol-3-phosphate acyltransferases (GPATs), and forms 1-acylglycerol-3-phosphate or lysophosphatidic acid (LPA). Further acylation of LPA at the sn-2 position by the enzymes called 1-acylglycerol-3-phosphate acyltransferases (AGPATs or LPAATs) results in formation of phosphatidic acid (PA). Phosphatidic acid phosphatases then remove the phosphate group from PA to produce diacylglycerol (DAG). Further acylation of DAG at the sn-3 position by the enzymes called diacylglycerol acyltransferases (DGATs) finally produces triacylglycerol (TG). The synthesis of glycerophospholipids uses the intermediates, PA and DAG. Phosphatidylinositol and cardiolipin can be formed from PA, whereas, phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine can be synthesized from DAG.

Fig. 3. Schematics of lipid droplet formation in adipocyte

Panel A shows the progressive formation of lipid droplet (LD) at the endoplasmic reticulum in normal cells. Shown also are the enzymes involved in the synthesis of triglycerides, although it is unclear if all the enzymes of the pathway are present at the LD. The small LDs in adipocytes fuse to form one or more large LDs. Shown also are proteins of PAT class which decorate the LD surface. Panel B shows the reduced triglyceride synthesis due to deficiency of one of the key enzymes, AGPAT2 in patients with congenital generalized lipodystrophy, type 1. Fusion of LDs may still occur, but at considerably reduced rate. It is likely that the LDs may be totally devoid of TG (shown in white) or minimal TG synthesis may occur utilizing other AGPAT isoforms. Other possibilities (not shown) are that LDs may not form due to lack of synthesis of LD surface glycerophospholipids or there may be total lack of adipocyte development due to lack of phospholipid synthesis required for formation of cell membrane and other organelles. In panel C, where the cells lack expression of seipin as happens in patients with congenital lipodystrophy, type 2, fusion of LDs may not occur, however, synthesis of triglyceride may still continue resulting in several small LDs instead of one or more large LDs.