Consequences of Lipid Droplet Coat Protein Downregulation in Liver Cells

Abnormal Lipid Droplet Metabolism and Induction of Insulin Resistance

  1. Ming Bell1,
  2. Hong Wang1,
  3. Hui Chen2,
  4. John C. McLenithan3,
  5. Da-Wei Gong3,
  6. Rong-Zee Yang3,
  7. Daozhan Yu3,
  8. Susan K. Fried3,
  9. Michael J. Quon2,
  10. Constantine Londos4 and
  11. Carole Sztalryd1
  1. 1Geriatric Research, Education and Clinical Center, Baltimore Veterans Affairs Health Care Center, Division of Gerontology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland
  2. 2Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland
  3. 3Division of Endocrinology, Department of Medicine, School of Medicine, University of Maryland, Baltimore, Maryland
  4. 4Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  1. Corresponding author: Carole Sztalryd, csztalry{at}


OBJECTIVE—Accumulation of intracellular lipid droplets (LDs) in non-adipose tissues is recognized as a strong prognostic factor for the development of insulin resistance in obesity. LDs are coated with perilipin, adipose differentiation–related protein, tail interacting protein of 47 kd (PAT) proteins that are thought to regulate LD turnover by modulating lipolysis. Our hypothesis is that PAT proteins modulate LD metabolism and therefore insulin resistance.

RESEARCH DESIGN AND METHODS—We used a cell culture model (murine AML12 loaded with oleic acid) and small interfering RNA to directly assess the impact of PAT proteins on LD accumulation, lipid metabolism, and insulin action. PAT proteins associated with excess fat deposited in livers of diet-induced obese (DIO) mice were also measured.

RESULTS—Cells lacking PAT proteins exhibited a dramatic increase in LD size and a decrease in LD number. Further, the lipolytic rate increased by ∼2- to 2.5-fold in association with increased adipose triglyceride lipase (ATGL) at the LD surface. Downregulation of PAT proteins also produced insulin resistance, as indicated by decreased insulin stimulation of Akt phosphorylation (P < 0.001). Phosphoinositide-dependent kinase-1 and phosphoinositide 3-kinase decreased, and insulin receptor substrate-1 307 phosphorylation increased. Increased lipids in DIO mice livers were accompanied by changes in PAT composition but also increased ATGL, suggesting a relative PAT deficiency.

CONCLUSIONS—These data establish an important role for PAT proteins as surfactant at the LD surface, packaging lipids in smaller units and restricting access of lipases and thus preventing insulin resistance. We suggest that a deficiency of PAT proteins relative to the quantity of ectopic fat could contribute to cellular dysfunction in obesity and type 2 diabetes.


  • Published ahead of print at on 16 May 2008.

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    • Accepted May 7, 2008.
    • Received February 8, 2008.
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  1. Diabetes vol. 57 no. 8 2037-2045
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