Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation.
Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxrα in mice with hepatocyte-specific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxrα produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxrα, and LXRα was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXRα to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXRα and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Xiaowei
X
Sun
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Mary E
ME
Haas
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Ji
J
Miao
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Abhiruchi
A
Mehta
Isis Pharmaceuticals, Carlsbad, California 92008.
Mark J
MJ
Graham
Isis Pharmaceuticals, Carlsbad, California 92008.
Rosanne M
RM
Crooke
the Centre de Recherche INSERM-UMR866, Université de Bourgogne, 21000 Dijon, France, and.
Jean-Paul
JP
Pais de Barros
the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Jian-Guo
JG
Wang
the Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Masanori
M
Aikawa
the Centre de Recherche INSERM-UMR866, Université de Bourgogne, 21000 Dijon, France, and.
David
D
Masson
From the Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, sudha.biddinger@childrens.harvard.edu.
Sudha B
SB
Biddinger
D000818:Animals; D003433:Crosses, Genetic; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000276:immunology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D006505:Hepatitis / Q000150:complications / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D000071518:Liver X Receptors; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011972:Receptor, Insulin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D007328:Insulin; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D011972:Receptor, Insulin
endoplasmic reticulum stress (ER stress); fructose; inflammation; insulin; insulin resistance; lipid metabolism; lipogenesis; liver X receptor; liver insulin-receptor knockout; lysophosphatidylcholine acyltransferase 3; phospholipid; phospholipid metabolism; selective insulin resistance