ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity[S]

Adipose tissue contains one of the largest reservoirs of cholesterol in the body. Adipocyte dysfunction in obesity is associated with intracellular cholesterol accumulation, and alterations in cholesterol homeostasis have been shown to alter glucose metabolism in cultured adipocytes. ABCA1 plays a major role in cholesterol efflux, suggesting a role for ABCA1 in maintaining cholesterol homeostasis in the adipocyte. However, the impact of adipocyte ABCA1 on adipose tissue function and glucose metabolism is unknown. Our aim was to determine the impact of adipocyte ABCA1 on adipocyte lipid metabolism, body weight, and glucose metabolism in vivo. To address this, we used mice lacking ABCA1 specifically in adipocytes (ABCA1−ad/−ad). When fed a high-fat, high-cholesterol diet, ABCA1−ad/−ad mice showed increased cholesterol and triglyceride stores in adipose tissue, developed enlarged fat pads, and had increased body weight. Associated with these phenotypic changes, we observed significant changes in the expression of genes involved in cholesterol and glucose homeostasis, including ldlr, abcg1, glut-4, adiponectin, and leptin. ABCA1−ad/−ad mice also demonstrated impaired glucose tolerance, lower insulin sensitivity, and decreased insulin secretion. We conclude that ABCA1 in adipocytes influences adipocyte lipid metabolism, body weight, and whole-body glucose homeostasis.

[1]  R. Wood-Bradley,et al.  White adipocytes: more than just fat depots. , 2012, The international journal of biochemistry & cell biology.

[2]  P. J. McFie,et al.  Murine Diacylglycerol Acyltransferase-2 (DGAT2) Can Catalyze Triacylglycerol Synthesis and Promote Lipid Droplet Formation Independent of Its Localization to the Endoplasmic Reticulum* , 2011, The Journal of Biological Chemistry.

[3]  B. Howard,et al.  Obesity and dyslipidemia. , 2003, Endocrinology and metabolism clinics of North America.

[4]  B. McManus,et al.  ABCA1 mRNA and Protein Distribution Patterns Predict Multiple Different Roles and Levels of Regulation , 2002, Laboratory Investigation.

[5]  P. Kovanen,et al.  Regulation of cholesterol synthesis and storage in fat cells. , 1975, Journal of lipid research.

[6]  S. Young,et al.  Biochemistry and pathophysiology of intravascular and intracellular lipolysis. , 2013, Genes & development.

[7]  Philip A Kern,et al.  Adipocytokines and the metabolic complications of obesity. , 2008, The Journal of clinical endocrinology and metabolism.

[8]  James D. Johnson,et al.  β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment , 2007, Nature Medicine.

[9]  M. Czech,et al.  Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes , 2008, Nature Reviews Molecular Cell Biology.

[10]  D. Savage.  Mouse models of inherited lipodystrophy , 2009, Disease Models & Mechanisms.

[11]  W. Soeller,et al.  Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. , 2003, Diabetes.

[12]  P. Ferré,et al.  New Insights into How Adipocytes Sense their Triglyceride Stores. Is Cholesterol a Signal? , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[13]  H. Lodish,et al.  Expression cloning of SR-BI, a CD36-related class B scavenger receptor. , 1994, The Journal of biological chemistry.

[14]  G. Steinberg,et al.  Adipose tissue as an endocrine organ , 2010, Molecular and Cellular Endocrinology.

[15]  G. Shulman,et al.  Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver , 2001, Nature.

[16]  M. Brown,et al.  Receptor-dependent hydrolysis of cholesteryl esters contained in plasma low density lipoprotein. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[17]  C. Gabel,et al.  High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Kahn,et al.  The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes , 2003, Diabetologia.

[19]  P. Ferré,et al.  Cholesterol, a Cell Size-dependent Signal That Regulates Glucose Metabolism and Gene Expression in Adipocytes* 210 , 2001, The Journal of Biological Chemistry.

[20]  E. L. Arrese,et al.  Characterization of apoA-I-dependent lipid efflux from adipocytes and role of ABCA1 , 2010, Molecular and Cellular Biochemistry.

[21]  J. Goldstein,et al.  Expression of the Familial Hypercholesterolemia Gene in Heterozygotes: Mechanism for a Dominant Disorder in Man , 1974, Science.

[22]  C. Sensen,et al.  Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency , 1999, Nature Genetics.

[23]  J. Jukema,et al.  Niacin Increases HDL by Reducing Hepatic Expression and Plasma Levels of Cholesteryl Ester Transfer Protein in APOE*3Leiden.CETP Mice , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[24]  P. Ferré,et al.  Regulation of ABCA1 expression and cholesterol efflux during adipose differentiation of 3T3-L1 cells Published, JLR Papers in Press, May 16, 2003. DOI 10.1194/jlr.M200466-JLR200 , 2003, Journal of Lipid Research.

[25]  M. Hayden,et al.  Specific Loss of Brain ABCA1 Increases Brain Cholesterol Uptake and Influences Neuronal Structure and Function , 2009, The Journal of Neuroscience.

[26]  M. Blüher,et al.  Adipose tissue dysfunction in obesity. , 2009, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[27]  Paul D Thomas,et al.  Accurate Prediction of the Functional Significance of Single Nucleotide Polymorphisms and Mutations in the ABCA1 Gene , 2005, PLoS genetics.

[28]  N. Maeda,et al.  Adipose Tissue ATP Binding Cassette Transporter A1 Contributes to High-Density Lipoprotein Biogenesis In Vivo , 2011, Circulation.

[29]  K. Lindor,et al.  Nonalcoholic fatty liver disease , 2005, Canadian Medical Association Journal.

[30]  B.-L. Yu,et al.  Cholesterol imbalance in adipocytes: a possible mechanism of adipocytes dysfunction in obesity , 2009, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[31]  Paul T. Tarr,et al.  ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. , 2005, Cell metabolism.

[32]  Devjit Tripathy,et al.  Defects in Insulin Secretion and Action in the Pathogenesis of Type 2 Diabetes Mellitus , 2010, Current diabetes reports.

[33]  F. Schaffner,et al.  Nonalcoholic fatty liver disease. , 1986, Progress in liver diseases.

[34]  P. Tontonoz,et al.  Liver X receptors as integrators of metabolic and inflammatory signaling. , 2006, The Journal of clinical investigation.

[35]  K. Eriksson,et al.  Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes , 2004, Diabetologia.