ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis.
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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3691114?pdf=render |
| _version_ | 1818477980058386432 |
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| author | Kazuhisa Watanabe Elizabeth Watson Maria Laura Cremona Elizabeth J Millings Jay H Lefkowitch Stuart G Fischer Charles A LeDuc Rudolph L Leibel |
| author_facet | Kazuhisa Watanabe Elizabeth Watson Maria Laura Cremona Elizabeth J Millings Jay H Lefkowitch Stuart G Fischer Charles A LeDuc Rudolph L Leibel |
| author_sort | Kazuhisa Watanabe |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T09:42:55Z |
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| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T09:42:55Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-404c84fb376d47839b7f217b0be667232022-12-22T01:53:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6723410.1371/journal.pone.0067234ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis.Kazuhisa WatanabeElizabeth WatsonMaria Laura CremonaElizabeth J MillingsJay H LefkowitchStuart G FischerCharles A LeDucRudolph L LeibelIldr2, 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.http://europepmc.org/articles/PMC3691114?pdf=render |
| spellingShingle | Kazuhisa Watanabe Elizabeth Watson Maria Laura Cremona Elizabeth J Millings Jay H Lefkowitch Stuart G Fischer Charles A LeDuc Rudolph L Leibel ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis. PLoS ONE |
| title | ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis. |
| title_full | ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis. |
| title_fullStr | ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis. |
| title_full_unstemmed | ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis. |
| title_short | ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis. |
| title_sort | ildr2 an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis |
| url | http://europepmc.org/articles/PMC3691114?pdf=render |
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