Anil Agarwal Lab

Dr. Agarwal's research focuses on mechanisms of steroid action, especially structure-activity relationships of ligand-steroid receptor interactions, and steroid metabolism.

Our most recent work relates to congenital generalized lipodystrophy, an autosomal recessive disorder characterized by extreme lack of body fat since birth, severe insulin resistance, hypertriglyceridemia, hepatic steatosis, and early onset of diabetes.

Through positional cloning, we identified disease-causing mutations in the AGPAT2 gene (located on chromosome 9q34, encoding 1-acylglycerol-3-phosphate-O-acyltransferase 2) in affected subjects from 26 of 42 pedigrees of various ethnicities.

The affected individuals were either homozygous or compound heterozygous for various mutations including, deletions, nonsense, missense, splice-site, and those in the 3’UTR. AGPAT2 catalyzes the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol (TG) and glycerophospholipids, which are involved in signal transduction.

The high AGPAT2 expression in adipose tissue suggests that the AGPAT2 mutations may cause CGL by inhibiting TG biosynthesis and storage in the adipocytes. It is also of interest to note that only five pedigrees revealed mutations in the BSCL2 gene located on chromosome 11q13. The function of BSCL2 remains unknown. These observations suggest that at least two distinct mechanisms may underlie the extreme lack of adipose tissue in CGL patients. In addition to these studies, they also showed in a pedigree with familial partial lipodystrophy a hyterozygous, R425C, a mutation in the PPARG gene. It is still unclear how such a mutation could cause regional loss of fat.

More recently we have determined a new genetic loci, a zinc metalloproteinase (ZMPSTE24), in subjects diagnosed with mandibuloacral dysplasia, a rare autosomal recessive disorder, that affects multiple tissues including loss of partial adipose tissue leading to insulin resistance and diabetes mellitus. These patients also have progeroid features. Mutations in ZMPSTE24 which is a coax-motif protease, cleaves prelamin A to mature lamin A. Uncleaved prelamin A is toxic to the cells.