The objective of Project 2 is to define the role of the lipin family of proteins in triglyceride metabolism. We previously identified mutations in lipin-1 as the cause of lipodystrophy in the fatty liver dystrophy mutant mouse strain, and established that lipin-1 is a determinant of adipose tissue development, obesity, and insulin sensitivity in mice and humans. Very recently, two distinct molecular functions for lipin-1 have been characterized. First, lipin-1 is a phosphatidate phosphatase-1 (PAP1) enzyme, catalyzing a key step in triglyceride biosynthesis, and accounting for all PAP1 activity in adipose tissue and skeletal muscle. Second, lipin-1 is a transcriptional coactivator of PPAR (peroxisome proliferator-activated receptor)-alpha and PPARgamma in hepatocytes and adipocytes. We have also identified two additional lipin family members and determined that they have PAP1 activity and exhibit prominent expression in liver (lipin-2) or bone (lipin-3). We hypothesize that each of the three lipin proteins has unique, tissue-specific roles in triglyceride metabolism through their actions as PAP1 enzymes and transcriptional coactivators.
The Specific Aims are: (1) To determine the mechanisms by which point mutations in mouse lipin-1 and human lipin-2 impair PAP1 and/or coactivator function to cause lipodystrophy and the inflammatory disorder, Majeed syndrome, respectively. (2) To determine the requirement for lipin-1 coactivator versus PAP1 function in adipocyte differentiation, physiology, and metabolism using genetic and chemical manipulation of lipin-1 activity. We will generate cultured cells and mice that express """"""""coactivator only"""""""" lipin-1 protein and determine ability of the mutant to complement lipin-1 deficiency in adipose tissue, liver, muscle, nerve, and reproductive function. We will also characterize the mechanism by which a novel adipogenic compound identified in Project 3 enhances PAP1 activity, and determine effects of other proadipogenic compounds on lipin-1 coactivator and PAP1 activity. (3) To establish the physiological roles of lipin-2 and lipin-3. We will generate knockout mouse models and characterize the role of lipin-2 in hepatic lipid metabolism and inflammation, and the role of lipin-3 in bone lipid metabolism and production of bone hormones that modulate systemic glucose homeostasis. The elucidation of lipin protein functions may lead to novel approaches for modulating adiposity, insulin sensitivity and inflammation contributing to obesity, hyperlipidemia, and diabetes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Kristensen, Kristian K; Midtgaard, Søren Roi; Mysling, Simon et al. (2018) A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proc Natl Acad Sci U S A 115:E6020-E6029
Allan, Christopher M; Heizer, Patrick J; Jung, Cris J et al. (2018) Palmoplantar keratoderma in Slurp1/Slurp2 double-knockout mice. J Dermatol Sci 89:85-87
He, Cuiwen; Weston, Thomas A; Jung, Rachel S et al. (2018) NanoSIMS Analysis of Intravascular Lipolysis and Lipid Movement across Capillaries and into Cardiomyocytes. Cell Metab 27:1055-1066.e3
Larsson, Mikael; Allan, Christopher M; Heizer, Patrick J et al. (2018) Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure. J Lipid Res 59:706-713
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Rajbhandari, Prashant; Thomas, Brandon J; Feng, An-Chieh et al. (2018) IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure. Cell 172:218-233.e17
He, Cuiwen; Hu, Xuchen; Weston, Thomas A et al. (2018) Macrophages release plasma membrane-derived particles rich in accessible cholesterol. Proc Natl Acad Sci U S A 115:E8499-E8508
Wang, Jiexin; Rajbhandari, Prashant; Damianov, Andrey et al. (2017) RNA-binding protein PSPC1 promotes the differentiation-dependent nuclear export of adipocyte RNAs. J Clin Invest 127:987-1004
He, Cuiwen; Hu, Xuchen; Jung, Rachel S et al. (2017) Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1. JCI Insight 2:
Nakano, Haruko; Minami, Itsunari; Braas, Daniel et al. (2017) Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. Elife 6:

Showing the most recent 10 out of 143 publications