Aberrant activation of liver X receptors impairs pancreatic beta cell function through upregulation of sterol regulatory element-binding protein 1c in mouse islets and rodent cell lines

Abstract

Aims/hypothesis Liver X receptors (LXR) are important transcriptional regulators of lipid and glucose metabolism. Our previous report demonstrated that LXR activation inhibited pancreatic beta cell proliferation through cell cycle arrest. Here we explore the role of LXR activation in beta cell insulin secretion and the underlying mechanism that might be involved. Methods Mouse pancreatic islets or insulin-secreting MIN6 cells were exposed to the LXR agonist, T0901317, and insulin secretion, glucose and fatty acid oxidation, and lipogenic gene expression were assessed. The unsaturated fatty acid eicosapentaenoic acid and the dominant negative sterol regulatory element binding protein 1c (SREBP1c) were used to inhibit endogenous SREBP1c and evaluate the involvement of SREBP1c in beta cell dysfunction induced by LXR activation. Results Treatment with the LXR agonist decreased beta cell glucose sensitivity and impaired glucose-stimulated insulin secretion in vivo and in vitro. This was accompanied by derangements of beta cell glucose oxygen consumption, glucose oxidation, ATP production and intracellular voltagegated calcium channel flux. LXR activation also regulated the expression of lipid metabolism-related genes such as Fas, Acc (also known as Acaca) and Cpt1a, and led to intracellular lipid accumulation. Further studies revealed that inhibition of SREBP1c abolished LXR activation-induced lipid accumulation and improved beta cell glucose metabolism, ATP production and insulin secretion. Conclusions/interpretation Our data reveal that aberrant activation of LXR reproduced the phenomenon of beta cell dysfunction in the development of type 2 diabetes in vitro and in vivo. Upregulation of SREBP1c production and the lipotoxicity mediated by it played a central role in this process.

Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

“…The role of LXR in regulating glucose tolerance in vivo is still somewhat controversial [26]. The LXR agonist used in this study was reported to improve glycaemic control in db/db mice and in Zucker fatty rats [27,28], but worsened glycaemic control in normal C57BL/6 mice [29]. Consistent with the latter finding, LXR-deficient mice had better glycaemic control when fed a western-style diet [30].…”

“…The discrepancy between these findings is difficult to explain, but the different dietary interventions used in each study might contribute to these differences because hepatic LXR is activated by the dietary cholesterol content in a dose-dependent manner [31]. In the present study, the FLS mice were fed a normal diet with a low cholesterol content, similar to the conditions used in an earlier report [29]. Under these conditions, LXR activation might overcome BAR-mediated suppression of LXR activity.…”

Lipotoxicity in the Pancreatic Beta Cell: Not Just Survival and Function, but Proliferation as Well?

“…The intracellular cholesterol transport protein Npc1, genetically associated with risk of obesity in humans, may also play a role in insulin secretion [56]. LXR alpha, a receptor for cholesterol-related compounds, is important for insulin secretion in vitro and in vivo by altering glucose metabolism, ATP production and calcium channel flux; modulating its activity deregulated lipid metabolism via SREBP [57]. …”

Regulation of Insulin Resistance and Adiponectin Signaling in Adipose Tissue by Liver X Receptor Activation Highlights a Cross-Talk with PPARγ

“…In these studies, positive outcomes are primarily mediated by inhibition of gluconeogenesis and limitation of glucose output from the liver; however, recent studies using LXR-knockout mice have demonstrated opposing results [8]–[9]. Furthermore, Meng et al [10] has shown decreased β cell glucose sensitivity and insulin secretion in response to LXR activation in vitro and deterioration of glucose tolerance in vivo manifested as suppressed insulin secretion in response to glucose injection. Another study has also demonstrated that LXR activation downregulated insulin-stimulated glucose uptake in human adipocytes from overweight individuals, which could be due to transcriptional suppression of several insulin signaling genes [11].…”