Cellular retinol-binding protein type III is a PPARγ target gene and plays a role in lipid metabolism

Abstract

Zizola CF, Schwartz GJ, Vogel S. Cellular retinol-binding protein type III is a PPAR␥ target gene and plays a role in lipid metabolism. Am J Physiol Endocrinol Metab 295: E1358 -E1368, 2008. First published October 7, 2008 doi:10.1152/ajpendo.90464.2008.-Cellular retinol-binding protein (CRBP) type III (CRBP-III) belongs to the family of intracellular lipid-binding proteins, which includes the adipocyte-binding protein aP2. In the cytosol, CRBP-III binds retinol, the precursor of retinyl ester and the active metabolite retinoic acid. The goal of the present work is to understand the regulation of CRBP-III expression and its role in lipid metabolism. Using EMSAs, luciferase reporter assays, and chromatin immunoprecipitation assays, we found that CRBP-III is a direct target of peroxisome proliferatoractivated receptor-␥ (PPAR␥). Moreover, CRBP-III expression was induced in adipose tissue of mice after treatment with the PPAR␥ agonist rosiglitazone. To examine a potential role of CRBP-III in regulating lipid metabolism in vivo, CRBP-III-deficient (C-III-KO) mice were maintained on a high-fat diet (HFD). Hepatic steatosis was decreased in HFD-fed C-III-KO compared with HFD-fed wild-type mice. These differences were partly explained by decreased serum free fatty acid levels and decreased free fatty acid efflux from adipose tissue of C-III-KO mice. In addition, the lack of CRBP-III was associated with reduced food intake, increased respiratory energy ratio, and altered body composition, with decreased adiposity and increased lean body mass. Furthermore, expression of genes involved in mitochondrial fatty acid oxidation in brown adipose tissue was increased in C-III-KO mice, and C-III-KO mice were more cold tolerant than wild-type mice fed an HFD. In summary, we demonstrate that CRBP-III is a PPAR␥ target gene and plays a role in lipid and whole body energy metabolism. adipose tissue; retinoid; liver steatosis; lipolysis; brown adipose tissue; fatty acid-binding protein; intracellular lipid-binding protein; retinol-binding protein-7

Hepatic retinol secretion and storage are altered by dietary CLA: common and distinct actions of CLA c9,t11 and t10,c12 isomers

“…To rule out that the excess retinol in the circulation bound to RBP upon CLA t10,c12 feeding is the result of vitamin A mobilization from the periphery of the body, we analyzed the retinoid status of the adipose tissue, another important site of retinoid storage that expresses RBP ( 11,(44)(45)(46). In wild-type mice, adipose RBP protein levels remained unaffected upon CLA feeding with either isomer ( Fig.…”

“…t10,c12 alters vitamin A metabolism in the target tissues. Among these, adipose tissue has been proposed to contribute signifi cantly to the regulation of whole body retinoid homeostasis (44)(45)(46). Therefore, we measured retinol and retinyl ester levels in fat tissue of wild-type mice ( 21 ).…”

Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue

“…The literature suggests linkages between retinoid storage, metabolism, and actions and the development of fatty liver. Included in this literature are studies reporting ablation of hepatic retinoid receptor signaling resulting in hepatic steatosis ( 55 ), ablation of carotenoid-15,15 ′ -oxygenase (which abolishes retinoid production from ␤ -carotene) ( 56 ), studies of mice defi cient in CRBPIII ( 57 ), nutritional studies carried out in mice or rats (58)(59)(60)(61), studies of retinoid…”

PPARγ in the endothelium regulates metabolic responses to high-fat diet in mice

“…Both Cd36 mRNA and CD36 protein levels were decreased approximately 80% in ECs from γEC/BM-KO versus γEC/BM-WT mice ( Figure 8E). Importantly, these mice manifest altered expression of other genes involved in FA/TG handling, including the canonical PPARγ-regulated adipocyte protein 2 (aP2 also known as FA-binding protein 4) as well as novel PPARγ targets glycosylphosphatidylinositol-anchored HDLbinding protein 1 (Gpihbp1), a cofactor for LPL action (26,27), and the cellular retinol-binding protein III (CRBP-III, also known as RBP7 in mice and RBP5 in humans) that is expressed in ECs and is a member of the FA-binding protein family (28)(29)(30) (Figure 8F). Endothelial lipase expression was not altered, making it an unlikely contributor to the increased HDL-cholesterol and total cholesterol…”