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CD36 mediates lipid accumulation in pancreatic beta cells under the duress of glucolipotoxic conditions: Novel roles of lysine deacetylases

机译：在糖脂毒性条件下CD36介导胰腺β细胞的脂质蓄积：赖氨酸脱乙酰酶的新作用

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摘要

The cluster of differentiation 36 (CD36) is implicated in the intake of long-chain fatty acids and fat storage in various cell types including the pancreatic beta cell, thus contributing to the pathogenesis of metabolic stress and diabetes. Recent evidence indicates that CD36 undergoes post-translational modifications such as acetylation-deacetylation. However, putative roles of such modifications in its functional activation and onset of beta cell dysregulation under the duress of glucolipotoxicity (GLT) remain largely unknown. Using pharmacological approaches, we validated, herein, the hypothesis that acetylation-deacetylation signaling steps are involved in CD36-mediated lipid accumulation and downstream apoptotic signaling in pancreatic beta (INS-1 832/13) cells under GLT. Exposure of these cells to GLT resulted in significant lipid accumulation without affecting the CD36 expression. Sulfo-n-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, significantly attenuated lipid accumulation under GLT conditions, thus implicating CD36 in this metabolic step. Furthermore, trichostatin A (TSA) or valproic acid (VPA), known inhibitors of lysine deacetylases, markedly suppressed GLT-associated lipid accumulation with no discernable effects on CD36 expression. Lastly, SSO or TSA prevented caspase 3 activation in INS-1 832/13 cells exposed to GLT conditions. Based on these findings, we conclude that acetylation-deacetylation signaling step might regulate CD36 functional activity and subsequent lipid accumulation and caspase 3 activation in pancreatic beta cells exposed to GLT conditions. Identification of specific lysine deacetylases that control CD36 function should provide novel clues for the prevention of beta-cell dysfunction under GLT.
机译：分化簇36（CD36）与长链脂肪酸的摄取和脂肪在各种类型的细胞（包括胰腺β细胞）中的储存有关，因此有助于代谢应激和糖尿病的发病。最近的证据表明CD36经历翻译后修饰，例如乙酰化-脱乙酰化。然而，在糖脂毒性（GLT）的胁迫下，这种修饰在其功能激活和β细胞失调发作中的推定作用仍然未知。在本文中，我们使用药理学方法验证了以下假设：乙酰化-去乙酰化信号转导步骤参与了GLT下胰腺β（INS-1 832/13）细胞中CD36介导的脂质蓄积和下游凋亡信号转导。将这些细胞暴露于GLT会导致大量脂质堆积，而不会影响CD36的表达。 CD36的不可逆抑制剂油酸正琥珀酰亚胺酯（SSO）在GLT条件下显着减弱了脂质积聚，从而使CD36参与了该代谢步骤。此外，已知的赖氨酸脱乙酰基酶抑制剂曲古抑菌素A（TSA）或丙戊酸（VPA）显着抑制了GLT相关的脂质蓄积，而对CD36表达没有明显影响。最后，SSO或TSA阻止了暴露于GLT条件的INS-1 832/13细胞中的caspase 3活化。基于这些发现，我们得出结论，乙酰化-去乙酰化信号转导步骤可能会调节CD36的功能活性，以及​​随后在暴露于GLT条件下的胰岛β细胞中脂质积累和caspase 3活化。控制CD36功能的特定赖氨酸脱乙酰基酶的鉴定应为预防GLT下β细胞功能异常提供新线索。

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