Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells.
Liver X receptor (LXR)alpha and LXRbeta play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic beta-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced beta-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in beta-cells as a possible cause of beta-cell lipotoxicity, a key step in the development of type 2 diabetes.
Choe
Sung Sik
SS
Department of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Sillim-Dong, Kwanak-Gu, Seoul, Korea.
Choi
A Hyun
AH
Lee
Joo-Won
JW
Kim
Kang Ho
KH
Chung
Jun-Jae
JJ
Park
Jiyoung
J
Lee
Kyeong-Min
KM
Park
Keun-Gyu
KG
Lee
In-Kyu
IK
Kim
Jae Bum
JB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005786:Gene Expression Regulation; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology*; D008055:Lipids / Q000502:physiology / Q000633:toxicity; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051381:Rats; D020334:Rats, Inbred OLETF; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D008055:Lipids; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D002784:Cholesterol