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Targeted Deletion of Adipocyte Abca1 (ATP-Binding Cassette Transporter A1) Impairs Diet-Induced Obesity.

ABSTRACT: OBJECTIVE:Adipose tissue cholesterol increases with adipocyte triglyceride content and size during development of obesity. However, how adipocyte cholesterol affects adipocyte function is poorly understood. The aim of this study was to evaluate the role of the cellular cholesterol exporter, Abca1 (ATP-binding cassette transporter A1), on adipose tissue function during diet-induced obesity. APPROACH AND RESULTS:Adiponectin Cre recombinase transgenic mice were crossed with Abca1flox/flox mice to generate ASKO (adipocyte-specific Abca1 knockout) mice. Control and ASKO mice were then fed a high-fat, high-cholesterol (45% calories as fat and 0.2% cholesterol) diet for 16 weeks. Compared with control mice, ASKO mice had a 2-fold increase in adipocyte plasma membrane cholesterol content and significantly lower body weight, epididymal fat pad weight, and adipocyte size. ASKO versus control adipose tissue had decreased PPAR? (peroxisome proliferator-activated receptor ?) and CCAAT/enhancer-binding protein expression, nuclear SREBP1 (sterol regulatory element-binding protein 1) protein, lipogenesis, and triglyceride accretion but similar Akt activation after acute insulin stimulation. Acute siRNA-mediated Abca1 silencing during 3T3L1 adipocyte differentiation reduced adipocyte Abca1 and PPAR? protein expression and triglyceride content. Systemic stimulated triglyceride lipolysis and glucose homeostasis were similar between control and ASKO mice. CONCLUSIONS:Adipocyte Abca1 is a key regulator of adipocyte lipogenesis and lipid accretion, likely because of increased adipose tissue membrane cholesterol, resulting in decreased activation of lipogenic transcription factors PPAR? and SREBP1.

SUBMITTER: Cuffe H

PROVIDER: S-EPMC5864538 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Targeted Deletion of Adipocyte Abca1 (ATP-Binding Cassette Transporter A1) Impairs Diet-Induced Obesity.

Cuffe Helen H Liu Mingxia M Key Chia-Chi C CC Boudyguina Elena E Sawyer Janet K JK Weckerle Allison A Bashore Alexander A Fried Susan K SK Chung Soonkyu S Parks John S JS

Arteriosclerosis, thrombosis, and vascular biology 20180118 4

<h4>Objective</h4>Adipose tissue cholesterol increases with adipocyte triglyceride content and size during development of obesity. However, how adipocyte cholesterol affects adipocyte function is poorly understood. The aim of this study was to evaluate the role of the cellular cholesterol exporter, Abca1 (ATP-binding cassette transporter A1), on adipose tissue function during diet-induced obesity.<h4>Approach and results</h4>Adiponectin <i>Cre</i> recombinase transgenic mice were crossed with <i ...[more]

PMID: 29348118

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Project description:Transplantation studies suggest that bone marrow cell ATP-binding cassette transporter A1 protects against atherosclerosis development. However, the in vivo effect of macrophage ATP-binding cassette transporter A1 expression on atherogenesis is not fully understood because bone marrow contains other leukocytes and hematopoietic stem and progenitor cells. Myeloid-specific ATP-binding cassette transporter A1 knockout mice in the low-density lipoprotein (LDL) receptor knockout C57BL/6 background were developed to address this question.Chow-fed myeloid-specific ATP-binding cassette transporter A1 knockout/LDL receptor knockout (double knockout [DKO]) versus LDL receptor knockout (single knockout [SKO]) mice had similar plasma lipid concentrations, but atherogenic diet (AD)-fed DKO mice had reduced plasma very-LDL (VLDL)/LDL concentrations resulting from decreased hepatic VLDL triglyceride secretion. Resident peritoneal macrophages from AD-fed DKO versus SKO mice had significantly higher cholesterol content but similar proinflammatory gene expression. Atherosclerosis extent was similar between genotypes after 10 to 16 weeks of AD but increased modestly in DKO mice by 24 weeks of AD. Lesional macrophage content was similar, likely because of the higher monocyte flux through aortic root lesions in DKO versus SKO mice. After transplantation of DKO or SKO bone marrow into SKO mice and 16 weeks of AD feeding, atherosclerosis extent was similar and plasma apolipoprotein B lipoproteins were reduced in mice receiving DKO bone marrow. When differences in plasma VLDL/LDL concentrations were minimized by maintaining mice on chow for 24 weeks, DKO mice had modest, but significantly more, atherosclerosis compared with SKO mice.Myeloid cell ATP-binding cassette transporter A1 increases hepatic VLDL triglyceride secretion and plasma VLDL/LDL concentrations in AD-fed LDL receptor knockout mice, offsetting its atheroprotective role in decreasing macrophage cholesterol content, resulting in a minimal increase in atherosclerosis.

Dataset Information

Targeted Deletion of Adipocyte Abca1 (ATP-Binding Cassette Transporter A1) Impairs Diet-Induced Obesity.

Publications

Targeted Deletion of Adipocyte Abca1 (ATP-Binding Cassette Transporter A1) Impairs Diet-Induced Obesity.

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