ArticleThe Journal of biological chemistry2014
Insig proteins mediate feedback inhibition of cholesterol synthesis in the intestine.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER.Cell metabolism · 2024Article
- Adverse outcome pathway for pregnane X receptor-induced hypercholesterolemia.Archives of toxicology · 2023Review
- A Multi-Level Systems Biology Analysis of Aldrin's Metabolic Effects on Prostate Cancer Cells.Proteomes · 2023Article
- Intestinal Deletion of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion of the Resident Stem Cell Compartment.Arteriosclerosis, thrombosis, and vascular biology · 2022Article
- Article
- Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption.Science advances · 2021Article
- The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.Journal of diabetes and metabolic disorders · 2020Review
- Hub Proteins Involved in RAW 264.7 Macrophages Exposed to Direct Current Electric Field.International journal of molecular sciences · 2020Article
- The cellular function of SCAP in metabolic signaling.Experimental & molecular medicine · 2020Review
- Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated witheLife · 2020Article
- Article
- Developmental and extrahepatic physiological functions of SREBP pathway genes in mice.Seminars in cell & developmental biology · 2018Review
- Dietary supplementation with olive mill wastewaters induces modifications on chicken jejunum epithelial cell transcriptome and modulates jejunum morphology.BMC genomics · 2018Article
- Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice.Journal of lipid research · 2018Article
- Hepatocyte-specific deletion of BAP31 promotes SREBP1C activation, promotes hepatic lipid accumulation, and worsens IR in mice.Journal of lipid research · 2018Article
- Overactivation of intestinal sterol response element-binding protein 2 promotes diet-induced nonalcoholic steatohepatitis.American journal of physiology. Gastrointestinal and liver physiology · 2017Article
- Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine.Journal of lipid research · 2017Article
- Hypoxia-inducible factor 1α activates insulin-induced gene 2 (Insig-2) transcription for degradation of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the liver.The Journal of biological chemistry · 2017Article
- CAT-2003: A novel sterol regulatory element-binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3-Leiden mice.Hepatology communications · 2017Article
- Contribution of Accelerated Degradation to Feedback Regulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Cholesterol Metabolism in the Liver.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
Enterocytes are the only cell type that must balance the de novo synthesis and absorption of cholesterol, although the coordinate regulation of these processes is not well understood. Our previous studies demonstrated that enterocytes respond to the pharmacological blockade of cholesterol absorption by ramping up de novo sterol synthesis through activation of sterol regulatory element-binding protein-2 (SREBP-2). Here, we genetically disrupt both Insig1 and Insig2 in the intestine, two closely related proteins that are required for the feedback inhibition of SREBP and HMG-CoA reductase (HMGR). This double knock-out was achieved by generating mice with an intestine-specific deletion of Insig1 using Villin-Cre in combination with a germ line deletion of Insig2. Deficiency of both Insigs in enterocytes resulted in constitutive activation of SREBP and HMGR, leading to an 11-fold increase in sterol synthesis in the small intestine and producing lipidosis of the intestinal crypts. The intestine-derived cholesterol accumulated in plasma and liver, leading to secondary feedback inhibition of hepatic SREBP2 activity. Pharmacological blockade of cholesterol absorption was unable to further induce the already elevated activities of SREBP-2 or HMGR in Insig-deficient enterocytes. These studies confirm the essential role of Insig proteins in the sterol homeostasis of enterocytes.
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