Liver X receptor agonists augment human islet function through activation of anaplerotic pathways and glycerolipid/free fatty acid cycling

Takeshi Ogihara, Jen Chieh Chuang, George L. Vestermark, James C. Garmey, Robert J. Ketchum, Xiaolun Huang, Kenneth L. Brayman, Michael O. Thorner, Joyce J. Repa, Raghu Mirmira, Carmella Evans-Molina

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5392-5404
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number8
DOIs
StatePublished - Feb 19 2010

Fingerprint

Nonesterified Fatty Acids
Liver
Chemical activation
Insulin
Gene Expression
Pyruvate Carboxylase
Sterol Esterase
Glucose
Lipogenesis
Gene encoding
Lipolysis
Enzyme activity
Enzymes
Nuclear Proteins
Liver X Receptors
Lipase
Pyruvic Acid
Gene expression
Rodentia
Triglycerides

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Liver X receptor agonists augment human islet function through activation of anaplerotic pathways and glycerolipid/free fatty acid cycling. / Ogihara, Takeshi; Chuang, Jen Chieh; Vestermark, George L.; Garmey, James C.; Ketchum, Robert J.; Huang, Xiaolun; Brayman, Kenneth L.; Thorner, Michael O.; Repa, Joyce J.; Mirmira, Raghu; Evans-Molina, Carmella.

In: Journal of Biological Chemistry, Vol. 285, No. 8, 19.02.2010, p. 5392-5404.

Research output: Contribution to journalArticle

Ogihara, Takeshi ; Chuang, Jen Chieh ; Vestermark, George L. ; Garmey, James C. ; Ketchum, Robert J. ; Huang, Xiaolun ; Brayman, Kenneth L. ; Thorner, Michael O. ; Repa, Joyce J. ; Mirmira, Raghu ; Evans-Molina, Carmella. / Liver X receptor agonists augment human islet function through activation of anaplerotic pathways and glycerolipid/free fatty acid cycling. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 8. pp. 5392-5404.
@article{ad68f293a3a94363b6a8e09255b4f41e,
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.",
author = "Takeshi Ogihara and Chuang, {Jen Chieh} and Vestermark, {George L.} and Garmey, {James C.} and Ketchum, {Robert J.} and Xiaolun Huang and Brayman, {Kenneth L.} and Thorner, {Michael O.} and Repa, {Joyce J.} and Raghu Mirmira and Carmella Evans-Molina",
year = "2010",
month = "2",
day = "19",
doi = "10.1074/jbc.M109.064659",
language = "English",
volume = "285",
pages = "5392--5404",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "8",

}

TY - JOUR

T1 - Liver X receptor agonists augment human islet function through activation of anaplerotic pathways and glycerolipid/free fatty acid cycling

AU - Ogihara, Takeshi

AU - Chuang, Jen Chieh

AU - Vestermark, George L.

AU - Garmey, James C.

AU - Ketchum, Robert J.

AU - Huang, Xiaolun

AU - Brayman, Kenneth L.

AU - Thorner, Michael O.

AU - Repa, Joyce J.

AU - Mirmira, Raghu

AU - Evans-Molina, Carmella

PY - 2010/2/19

Y1 - 2010/2/19

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77949316652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949316652&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.064659

DO - 10.1074/jbc.M109.064659

M3 - Article

C2 - 20007976

AN - SCOPUS:77949316652

VL - 285

SP - 5392

EP - 5404

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 8

ER -