Apolipoprotein A‐l improves pancreatic β‐cell function independent of the ATP‐binding cassette transporters ABCA1 and ABCG1

Abstract

Apolipoprotein A‐I (apoA‐I), the main protein constituent of HDLs, increases insulin synthesis and insulin secretion in pancreatic β cells. ApoA‐I also accepts cholesterol that effluxes from cells expressing ATP‐binding cassette transporter A1 (ABCA1) and ATP‐binding cassette transporter G1 (ABCG1). Mice with conditional deletion of ABCA1 and ABCG1 in β cells [β‐double knockout (DKO) mice] have increased islet cholesterol levels and reduced glucose‐stimulated insulin secretion (GSIS). The project asks whether metabolic pathways are dys‐regulated in β‐DKO mouse islets and whether this can be corrected, and GSIS improved, by treatment with apoA‐I. β‐DKO mice were treated with apoA‐I or PBS, and islets were isolated for determination of GSIS. Total RNA was extracted from β‐DKO and control mouse islets for microarray analysis. Metabolic pathways were interrogated by functional enrichment analysis. ApoA‐I treatment improved GSIS in β‐DKO but not control mouse islets. Plasma lipid and lipoprotein levels and islet cholesterol levels were also unaffected by treatment with apoA‐I. Cholesterol metabolism, glucose metabolism, and inflammation pathways were dysregulated in β‐DKO mouse islets. This was not corrected by treatment with apoA‐I. In summary, apoA‐I treatment improves GSIS by a cholesterol‐independent mechanism, but it does not correct metabolic dysregulation in β‐DKO mouse islets.—Hou, L., Tang, S., Wu, B. J., Ong, K.‐L., Westerterp, M., Barter, P. J., Cochran, B. J., Tabet, F., Rye, K.‐A. Apolipoprotein A‐I improves pancreatic β‐cell function independent of the ATP‐binding cassette transporters ABCA1 and ABCG1. FASEB J. 33, 8479–8489 (2019). http://www.fasebj.org

HDL Cholesterol and Non-Cardiovascular Disease: A Narrative Review

“…HDL has further been suggested to influence pancreatic β-cell function and survival ( Figure 2 , right part). The deletion of either ABCA1 or ABCG1 in β-cells in mice have resulted in increased intracellular cholesterol levels and thus impaired insulin secretion [ 117 , 118 , 119 ]. Robust evidence from the general population has not confirmed that these findings in mice translate into increased risk of type II diabetes in humans [ 120 ].…”

High Density Lipoproteins and Diabetes

“…However, the precise mechanism by which apoA-I improves β-cell function in this animal model has yet to be elucidated. What we do know is that the observed benefit is not related to the restoration of β-cell cholesterol homeostasis in the case of mice with conditional deletion of ABCA1 and ABCG1 in β-cells [24]. Nor is it related to improved glucose metabolism or to the inhibition of inflammation [24].…”

“…Evidence that the antidiabetic functions of apoA-I and apoA-II translate into improved glycaemic control in vivo is mounting. For example, lipid-free apoA-I treatment increases glucose-stimulated insulin secretion (GSIS) in C57BL6 mice with diet-induced obesity, and in isolated islets from mice with elevated islet cholesterol levels and impaired insulin secretion due to the conditional deletion of the ATP binding cassette transporters, ABCA1 and ABCG1, which export cholesterol from β-cells to lipid-free/lipid-poor apoA-I and HDLs, respectively [24,26,27,79]. However, the precise mechanism by which apoA-I improves β-cell function in this animal model has yet to be elucidated.…”

“…This has led to extensive investigation into a potential role for HDLs in the treatment of inflammatory diseases and diseases where oxidative stress is a key component, such as arthritis [21], cancer [20] and inflammatory bowel disease [22]. One of the most unexpected and important beneficial functions of HDLs to have emerged in recent years is the discovery that HDLs and some of their constituent apolipoproteins have potent antidiabetic properties [22][23][24][25][26][27][28].…”

Association between ABC family variants rs1800977, rs4149313, and rs1128503 and susceptibility to type 2 diabetes in a Chinese Han population

“…ATP-binding cassette transporter A1 (ABCA1) is a member of the ATP-binding cassette transporter family which binds and hydrolyzes ATP, using the energy generated to transport substances including lipids, sterols, and cell metabolites. [6][7][8] ABCA1 was previously shown to play a key role in the reverse transport of cholesterol. 9 Recent studies have shown that ABCA1 is essential for normal glucose regulation, such as on islet b cells.…”