Physiological Consequences of Compartmentalized Glycerolipid Synthesis Public Deposited

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  • March 19, 2019
Creator
  • Cooper, Daniel
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • The metabolic derangements present in type 2 diabetes are associated with the accumulation of triacylglycerol (TAG) in adipose and non-adipose tissues. However, the mechanisms whereby TAG accumulation drives pathogenesis remain obscure. The synthesis of TAG and other glycerolipids is initiated by the rate-limiting enzyme, glycerol-3-phosphate acyltransferase (GPAT), which catalyzes the esterification of an acyl-CoA to the sn-1 position of the glycerol-3-phosphate backbone. Four mammalian GPAT isoforms, each the product of a separate gene, have been discovered and recent evidence suggests that each GPAT isoform performs a unique function in directing glycerolipid synthesis. To test this hypothesis, we investigated the role of different GPAT isoforms in liver and brown adipose lipid metabolism, and adipocyte differentiation. First, we compared the unique functions of the major hepatic GPAT isoforms, GPAT1 and GPAT4. Although these isoforms contribute a similar amount of total GPAT activity in liver, GPAT1, but not GPAT4, was required for the incorporation of de novo synthesized fatty acids (FA) into TAG and to divert FA away from β-oxidation. Next, we elucidated the mechanism whereby mice lacking GPAT4 are protected from diet-induced obesity. GPAT4 is a major GPAT isoform in BAT, comprising approximately 65% of the total GPAT activity. In primary brown adipocytes lacking GPAT4 exogenous oleate was oxidized at a 46% higher rate than controls, suggesting that Gpat4-/- mice are protected from diet-induced obesity because GPAT4 in brown adipose tissue is required to limit the oxidation of exogenous FA. Finally, we provide evidence that the lipodystrophy-associated protein Seipin is an evolutionarily conserved regulator of GPAT activity. Seipin and its yeast ortholog, Fld1, physically interacted with GPAT and the loss of Seipin was associated with increased GPAT activity because GPAT had a higher affinity for one of its substrates, glycerol-3-phosphate. Seipin deficiency impairs adipogenesis and alters lipid droplet morphology and in 3T3L1 preadipocytes, GPAT overexpression recapitulated these effects, suggesting that increased GPAT activity is the underlying cause of the impaired adipogenesis and altered lipid droplet morphology. Taken together, these results suggest that the functions of each GPAT isoform are linked to specific physiological processes and that glycerolipid synthesis is highly compartmentalized.
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  • In Copyright
Advisor
  • Makowski, Liza
  • Klett, Eric
  • Hursting, Stephen
  • Coleman, Rosalind
  • Lund, Pauline Kay
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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