title: 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.
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ogihara
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chuang
authors.forename: George L
authors.initials: GL
authors.lastname: Vestermark
authors.forename: James C
authors.initials: JC
authors.lastname: Garmey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ketchum
authors.forename: Xiaolun
authors.initials: X
authors.lastname: Huang
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Brayman
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Repa
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
mesh_terms: D000293:Adolescent; D000328:Adult; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D050155:Lipogenesis / Q000187:drug effects / Q000502:physiology; D000071518:Liver X Receptors; D008297:Male; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D011766:Pyruvate Carboxylase / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013549:Sweetening Agents / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001565:Benzoates; D001596:Benzylamines; D005230:Fatty Acids, Nonesterified; D005947:Glucose; D005989:Glycerides; D018398:Homeodomain Proteins; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011766:Pyruvate Carboxylase; D019289:Pyruvic Acid; D013449:Sulfonamides; D013549:Sweetening Agents; D015534:Trans-Activators; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C084010:pancreatic and duodenal homeobox 1 protein