Making the Best of a Competition: the CREB3L3–SREBP Axis in Arteriosclerosis
| Autor: | Tirthadipa Pradhan-Sundd |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Arteriosclerosis SREBP sterol regulatory element-binding protein CREB3L3 FGF21 fibroblast growth factor 21 Bioinformatics CREB3L3 cAMP responsive element-binding protein 3 like 3 Mice Enterohepatic Circulation Cyclic AMP Response Element-Binding Protein Insig insulin-induced gene Original Research GFP green fluorescent protein Mice Knockout Sterol Regulatory Element Binding Proteins TBA total bile acid WD Western diet TG triglyceride Chemistry Gastroenterology Editorial Hyperlipidemia LPL lipoprotein lipase Female lipids (amino acids peptides and proteins) Sterol Regulatory Element Binding Protein 1 HDL high-density lipoprotein Hyperlipidemias SREBP ER endoplasmic reticulum Competition (economics) Tg transgenic FFA free fatty acid medicine Animals Humans lcsh:RC799-869 KO knockout PPARα peroxisome proliferator-activated receptor alpha Hepatology PLA proximity ligation assay S1P site-1 protease Lipogenesis SREBF sterol regulatory element-binding factor VLDL very-low-density lipoprotein Atherosclerosis Lipid Metabolism medicine.disease Sterol regulatory element-binding protein Mice Inbred C57BL TC total cholesterol Gene Expression Regulation Receptors LDL Apo apolipoprotein HPLC high-performance liquid chromatography HSV herpes simplex virus lcsh:Diseases of the digestive system. Gastroenterology LXR liver X receptor |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 11, Iss 4, Pp 1199-1201 (2021) |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2021.01.002 |
| Popis: | Background & Aims cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)–mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor–regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. Conclusions CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions. Graphical abstract |
| Databáze: | OpenAIRE |
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