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

• Published in: Journal of lipid research Vol. 58; no. 12; pp. 2348 - 2364
• Main Authors: Pelosi, Michele, Testet, Eric, Le Lay, Soazig, Dugail, Isabelle, Tang, Xiaoyun, Mabilleau, Guillaume, Hamel, Yamina, Madrange, Marine, Blanc, Thomas, Odent, Thierry, McMullen, Todd P.W., Alfò, Marco, Brindley, David N., de Lonlay, Pascale
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2017; Journal of Lipid Research; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Acid phosphatase; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; adipogenic differentiation; Adipose tissue; Adipose Tissue, White - cytology; Adipose Tissue, White - metabolism; Adolescent; Alleles; Body Fat Distribution; Body Weight; Case-Control Studies; Cell Differentiation; Child; Child, Preschool; Female; Gene expression; Gene Expression Regulation; human fat lipid analysis; human lipids; Humans; inborn errors of metabolism; Life Sciences; Lipids; lipodystrophies; Lipodystrophy; Lpin1 gene; Magnesium; Male; Mesenchyme; Middle Aged; Mutation; Patient-Oriented and Epidemiological Research; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxisome proliferator-activated receptors; phosphatases/lipid; Phosphatidate Phosphatase - deficiency; Phosphatidate Phosphatase - genetics; Phosphatidic acid; PPAR gamma - genetics; PPAR gamma - metabolism; Rhabdomyolysis; Rhabdomyolysis - genetics; Rhabdomyolysis - metabolism; Rhabdomyolysis - pathology; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; lipodystrophies; inborn errors of metabolism; phosphatases/lipid; adipogenic differentiation; human fat lipid analysis; human lipids; adipocytes; gene expression; Lipodystrophies; Gene Expression; Phosphatases/Lipid; Adipose tissue; Inborn errors of metabolism; Human fat lipid analysis; Human lipids; Adipogenic differentiation; Adipocytes; Lipin-1
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.P075440

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.