Normal human adipose tissue functions and differentiation in patients with biallelic LPIN1 inactivating mutations

Michele Pelosi,Eric Testet,Soazig Le Lay,Isabelle Dugail,Xiaoyun Tang,Guillaume Mabilleau,Yamina Hamel,Marine Madrange,Thomas Blanc,Thierry Odent,Todd P.W Mcmullen,Marco Alfò,David N Brindley,Pascale De Lonlay

doi:10.1194/jlr.p075440

Abstract

Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Mice carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known about the roles of lipin-1 in human adipocyte physiology. Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical, and gene expression analysis of adipose tissue biopsies from human patients harboring LPIN1 biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids. The increased expression of key adipogenic determinants such as SREBP1, PPARG, and PGC1A shows that specific compensatory phenomena can be activated in vivo in human adipocytes with deficiency of functional lipin-1.

Highlights

Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation
Mice carrying inactivating mutations of the Lpin1 gene are characterized by manifested lipodystrophy features, with a severe reduction of total fat mass, presence of abnormal adipocytes with multilocular lipid droplet (LD), and a significant increase of immature adipocytes in the adipose tissue [2, 7, 14]
We used human fat biopsies from patients carrying inactivating mutations in the LPIN1 gene in both alleles to explore whether impairment of lipin-1 is associated with metabolic, developmental, or histopathological defects that can be ascribed to lipodystrophy or adipose tissue deficiencies

Summary

Introduction

Lipin-1 is a Mg2+-dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Normal human adipose tissue functions and differentiation in patients with biallelic LPIN1 inactivating mutations. Studies in vitro and in vivo using mouse models show that the protein lipin-1, encoded by the gene Lpin, is an enzyme necessary for normal glycerolipid biosynthesis, which is able to control adipocyte metabolism and adipogenic differentiation [1,2,3,4,5,6,7].

Methods

Results

Conclusion