Liver X Receptor Agonists Augment Human Islet Function through Activation of Anaplerotic Pathways and Glycerolipid/Free Fatty Acid Cycling

Abstract

Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use.The liver X receptors (LXRs), 2 LXR␣ (NR1H3), and LXR␤ (NR1H2) are members of the nuclear hormone receptor superfamily and function to integrate lipid metabolic and inflammatory signaling (1). Upon binding to oxysterol ligands and heterodimerization with retinoid X receptors, LXRs bind to conserved LXR-responsive elements in target genes to regulate their expression. LXRs augment lipogenesis through transcriptional up-regulation of the genes encoding sterol regulatory binding-protein 1c (SREBP-1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD). They also function to regulate reverse cholesterol transport through the induction of genes encoding the ATP binding cassette transporters (ABCs) (2, 3). Furthermore, LXRs contribute to the regulation of innate immunity and have anti-inflammatory effects that are mediated through repression of several downstream targets of NF-B (nuclear factor light chain-enhancer of activated B cells) (4, 5).In addition to these well described effects on lipid metabolism and inflammation, LXRs also appear to play a role in the maintenance of glucose homeostasis. Oral administration of synthetic LXR agonists to diabetic rodent models, including obese db/db mice and Zucker fatty rats, results in improved glucose tolerance (6, 7). These effects of LXR agonists appear to arise in part from actions on insulin-sensitive tissues, as LXRs have been shown to enhance...

Supplement of TCA cycle intermediates protects against high glucose/palmitate-induced INS-1 beta cell death

“…Recent report stating that an LXR agonist could augment anaplerotic pathway through enhanced activation of PC may explain our result that T0901317 had strong protective effect on HG/PA-induced death (Supplemental Fig. 2D), even though its enhanced lipogenic activity [47]. Furthermore, a report that over-expression of PPAR up-regulated expression of anaplerotic pyruvate carboxylase [48] also suggests that FAO stimulation can also up-regulate the anaplerotic process, supporting that FAO stimulators protect against HG/PA-induced glucolipotoxicity through a sufficient supply of TCA cycle intermediates.…”

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

“…Appropriate LXR activity is important for whole-body energy metabolism and proper beta cell function [29,30], but chronic LXR activation has been reported to be involved in increased beta cell apoptosis [14,31]. Our previous study also found that chronic LXR hyperactivation could inhibit beta cell proliferation through cell cycle arrest [13].…”

“…Both cell lines exhibit glucose-inducible insulin secretion and retain physiological characteristics of normal beta cells. MIN6 cells (passages [20][21][22][23][24][25][26][27][28][29][30] were grown in DMEM medium containing 15% FBS (vol./vol. ), 25 mmol/l glucose, 50 μmol/l 2-mercaptoethanol, 100 U/ml penicillin and 100 μg/ml streptomycin [32].…”

Pancreatic and Duodenal Homeobox Protein 1 (Pdx-1) Maintains Endoplasmic Reticulum Calcium Levels through Transcriptional Regulation of Sarco-endoplasmic Reticulum Calcium ATPase 2b (SERCA2b) in the Islet β Cell

“…Cell Culture and in Vitro Islet Treatment-INS-1 832/13 rat insulinoma cells were cultured as described previously (36,37). NIH-3T3 immortalized mouse fibroblast cells were cultured at 37°C and 5% CO 2 in DMEM supplemented with 10% fetal bovine serum and 100 units/ml penicillin (38).…”