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OXPAT/PAT-1 Is a PPAR-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization

¹ Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
² Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
³ Division of Endocrinology, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, Arkansas
⁴ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence and reprint requests to Perry E. Bickel, Departments of Medicine and of Cell Biology and Physiology, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110. E-mail: pbickel{at}im.wustl.edu

Abbreviations: Acadm, medium-chain acyl-CoA dehydrogenase; Acadv1, very-long-chain acyl-CoA dehydrogenase; BAT, brown adipose tissue; Cox4, cytochrome C oxidase 4; EST, expressed sequence tag; IBMX, 3-isobutyl-1-methylxanthine; LCFA, long-chain fatty acid; PAT, perilipin, adipophilin, and TIP47; PPAR, peroxisome proliferator–activated receptor; Sdha, subunit a of succinate dehydrogenase; STZ, streptozotocin; TAG, triacylglycerol; TZD, thiazolidinedione; WAT, white adipose tissue

Lipid droplet proteins of the PAT (perilipin, adipophilin, and TIP47) family regulate cellular neutral lipid stores. We have studied a new member of this family, PAT-1, and found that it is expressed in highly oxidative tissues. We refer to this protein as "OXPAT." Physiologic lipid loading of mouse liver by fasting enriches OXPAT in the lipid droplet tissue fraction. OXPAT resides on lipid droplets with the PAT protein adipophilin in primary cardiomyocytes. Ectopic expression of OXPAT promotes fatty acid–induced triacylglycerol accumulation, long-chain fatty acid oxidation, and mRNAs associated with oxidative metabolism. Consistent with these observations, OXPAT is induced in mouse adipose tissue, striated muscle, and liver by physiological (fasting), pathophysiological (insulin deficiency), pharmacological (peroxisome proliferator–activated receptor [PPAR] agonists), and genetic (muscle-specific PPAR overexpression) perturbations that increase fatty acid utilization. In humans with impaired glucose tolerance, PPAR agonist treatment induces adipose OXPAT mRNA. Further, adipose OXPAT mRNA negatively correlates with BMI in nondiabetic humans. Our collective data in cells, mice, and humans suggest that OXPAT is a marker for PPAR activation and fatty acid oxidation. OXPAT likely contributes to adaptive responses to the fatty acid burden that accompanies fasting, insulin deficiency, and overnutrition, responses that are defective in obesity and type 2 diabetes.

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