Effect of TNF-α on the expression of ABCA1 in pancreatic β-cells

Abstract

ATP-binding cassette transporter A1 (ABCA1), a 254-kD membrane protein, is a key regulator of lipid efflux from cells to apolipoproteins. ABCA1 in pancreatic β-cells influences insulin secretion and cholesterol homeostasis. Tumor necrosis factor (TNF)-α is a pleiotropic cytokine that elicits a wide spectrum of physiological events, including cell proliferation, differentiation, and apoptosis, and is also known to decrease glucose-dependent insulin secretion in pancreatic islets. In the present study, we examined the role of TNF-α on ABCA1 expression in rat pancreatic islets and INS-1 cells. ABCA1 protein levels decreased in response to rising concentrations of TNF-α in pancreatic islets. Real-time polymerase chain reaction analysis showed a significant decrease in ABCA1 mRNA expression. In parallel with its effect on endogenous ABCA1 mRNA levels, TNF-α suppressed the activity of a reporter construct containing the ABCA1 promoter. This effect was abrogated by BIRB796, but not by SB203580 or PD98095. The constitutively active form of p38 mitogen-activated protein kinase (MAPK) γ suppressed ABCA1 promoter activity but not p38-MAPK (α, β), while a dominant-negative mutant of p38-MAPK γ blocked the effect of TNF-α on ABCA1 promoter activity. BIRB796 inhibited the increased cholesterol ester content induced by TNF-α. However, BIRB796 had no effect on the decreased insulin content nor ABCA1 suppression caused by TNF-α in INS-1 cells. In summary, TNF-α suppressed the expression of endogenous ABCA1 in pancreatic islets and INS-1 cells. These findings raise the possibility that TNF-α may affect insulin secretion by controlling ABCA1 expression.

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

“…Furthermore, p38α directly affects the glucose uptake in pancreatic β-cells through TSH signaling by up-regulating the expression of GLUT2 gene [ 188 ]. Finally, p38γ may have an important role in TNFα-mediated downregulation of ATP-binding cassette transporter A1 (ABCA1) expression, leading to suppression of insulin secretion [ 189 ].…”

“…Findings from different laboratories present an ambiguous picture of the role of p38α in browning and thermogenesis [ 173 , 176 , 177 ]. Similar to adipocytes, p38 isoforms present various functions in pancreatic β-cells and skeletal muscle [ 186 , 187 , 188 , 189 , 207 , 208 ]. In pancreatic β-cells, p38δ/γ suppress insulin secretion [ 186 , 187 , 189 ], whereas p38α promotes glucose uptake [ 188 ].…”

“…Similar to adipocytes, p38 isoforms present various functions in pancreatic β-cells and skeletal muscle [ 186 , 187 , 188 , 189 , 207 , 208 ]. In pancreatic β-cells, p38δ/γ suppress insulin secretion [ 186 , 187 , 189 ], whereas p38α promotes glucose uptake [ 188 ]. In skeletal muscle cells, p38γ stimulates glucose uptake [ 207 ].…”

Knockdown of GAS5 Inhibits Atherosclerosis Progression via Reducing EZH2-Mediated ABCA1 Transcription in ApoE−/− Mice

“…EZH2 can promote the progression of atherosclerosis by regulating ATP-binding cassette transporter A1 (ABCA1) transcription in atherosclerosis 16 . ABCA1 is a protein that has been implicated in the pathology of atherosclerosis, capable of regulating lipid efflux 17 . ABCA1 is also a key transporter in reverse-transportation of cholesterol, and overexpression of ABCA1 can inhibit the progression of atherosclerosis 18 .…”

The cytokine alterations/abnormalities and oxidative damage in the pancreas during hypertension development

“…These proteins also direct ductal-to-endocrine cell differentiation, with implications for β cell regeneration (via STAT3-dependent NGN3 activation) [74]. In the mature pancreas, cytokines such as IL-1β, IL-6, TNF-α, and TGF-β seem to be involved in the regulation of pancreatic chemokine, insulin, and/or glucagon secretion [4, 8, 41, 64] while chemokine MCP-1 which is constitutively present in pancreatic islet cells might play a role as a chemotactic factor [56]. The role of cytokines/chemokines in the pancreatic homeostasis may demonstrate among others studies on p38 mitogen-activated protein kinase which upregulates various cytokines and chemokines including IL-6, TNF-α, and MCP-1 [6] and at the same time suppresses chronic pancreatitis [77].…”