title: Adipocyte-specific overexpression of retinol-binding protein 4 causes hepatic steatosis in mice.
abstract: There is considerable evidence that both retinoids and retinol-binding protein 4 (RBP4) contribute to the development of liver disease. To understand the basis for this, we generated and studied transgenic mice that express human RBP4 (hRBP4) specifically in adipocytes. When fed a chow diet, these mice show an elevation in adipose total RBP4 (mouse RBP4 + hRBP4) protein levels. However, no significant differences in plasma RBP4 or retinol levels or in hepatic or adipose retinoid (retinol, retinyl ester, and all-trans-retinoic acid) levels were observed. Strikingly, male adipocyte-specific hRBP4 mice fed a standard chow diet display significantly elevated hepatic triglyceride levels at 3-4 months of age compared to matched littermate controls. When mice were fed a high-fat diet, this hepatic phenotype, as well as other metabolic phenotypes (obesity and glucose intolerance), worsened. Because adipocyte-specific hRBP4 mice have increased tumor necrosis factor-α and leptin expression and crown-like structures in adipose tissue, our data are consistent with the notion that adipose tissue is experiencing RBP4-induced inflammation that stimulates increased lipolysis within adipocytes. Our data further establish that elevated hepatic triglyceride levels result from increased hepatic uptake of adipose-derived circulating free fatty acids. We obtained no evidence that elevated hepatic triglyceride levels arise from increased hepatic de novo lipogenesis, decreased hepatic free fatty acid oxidation, or decreased very-low-density lipoprotein secretion.
  
  
  
  Our investigations establish that RBP4 expressed in adipocytes induces hepatic steatosis arising from primary effects occurring in adipose tissue. (Hepatology 2016;64:1534-1546).
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Lee
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Yuen
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY. wsb2@cumc.columbia.edu.
authors.forename: William S
authors.initials: WS
authors.lastname: Blaner
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue; D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000209:etiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity; D054839:Retinol-Binding Proteins, Plasma / Q000096:biosynthesis*
chemical_list: C101326:RBP4 protein, human; D054839:Retinol-Binding Proteins, Plasma