title: ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis.
abstract: Ildr2, a modifier of diabetes susceptibility in obese mice, is expressed in most organs, including islets and hypothalamus, with reduced levels in livers of diabetes-susceptible B6.DBA mice congenic for a 1.8 Mb interval of Chromosome 1. In hepatoma and neuronal cells, ILDR2 is primarily located in the endoplasmic reticulum membrane. We used adenovirus vectors that express shRNA or are driven by the CMV promoter, respectively, to knockdown or overexpress Ildr2 in livers of wild type and ob/ob mice. Livers in knockdown mice were steatotic, with increased hepatic and circulating triglycerides and total cholesterol. Increased circulating VLDL, without reduction in triglyceride clearance suggests an effect of reduced hepatic ILDR2 on hepatic cholesterol clearance. In animals that overexpress Ildr2, hepatic triglyceride and total cholesterol levels were reduced, and strikingly so in ob/ob mice. There were no significant changes in body weight, energy expenditure or glucose/insulin homeostasis in knockdown or overexpressing mice. Knockdown mice showed reduced expression of genes mediating synthesis and oxidation of hepatic lipids, suggesting secondary suppression in response to increased hepatic lipid content. In Ildr2-overexpressing ob/ob mice, in association with reduced liver fat content, levels of transcripts related to neutral lipid synthesis and cholesterol were increased, suggesting "relief" of the secondary suppression imposed by lipid accumulation. Considering the fixed location of ILDR2 in the endoplasmic reticulum, we investigated the possible participation of ILDR2 in ER stress responses. In general, Ildr2 overexpression was associated with increases, and knockdown with decreases in levels of expression of molecular components of canonical ER stress pathways. We conclude that manipulation of Ildr2 expression in liver affects both lipid homeostasis and ER stress pathways. Given these reciprocal interactions, and the relatively extended time-course over which these studies were conducted, we cannot assign causal primacy to either the effects on hepatic lipid homeostasis or ER stress responses.
authors.affiliation: Naomi Berrie Diabetes Center and Department of Pediatrics, Columbia University, New York, New York, United States of America.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Watanabe
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Watson
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Cremona
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Millings
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkowitch
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Fischer
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D000818:Animals; D002151:Calorimetry; D002784:Cholesterol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008074:Lipoproteins / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D014280:Triglycerides / Q000378:metabolism
chemical_list: C586074:ILDR2 protein, mouse; C583885:Ildr1 protein, mouse; D008074:Lipoproteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D014280:Triglycerides; D002784:Cholesterol