ArticleThe Journal of clinical investigation2021
CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Triglyceride-Rich Lipoprotein Metabolism and Cardiovascular Risk in Diabetes: Bedside to Bench to Bedside.Circulation research · 2026Review
- Sex-specific KDM6A-HNF4A-CREBH network controls lipoprotein cholesterol metabolism and atherosclerosis via epigenetic reprograming of hepatocytes.Nature communications · 2026Article
- Soluble Triggering Receptor Expressed on Myeloid Cells 2 is a Biomarker but Not a Mediator of Fibrosing Steatohepatitis.Gastro hep advances · 2026Article
- Elevated apolipoprotein C3 heightens atherosclerosis risk by mediating arterial accumulation of free cholesterol and local inflammation in diabetes.Research square · 2025Article
- Effect of complete, lifelong ANGPTL3 deficiency on triglyceride-rich lipoprotein kinetics.Cell reports. Medicine · 2025Article
- Cgref1 is a CREB-H-regulated hepatokine that promotes hepaticInternational journal of biological sciences · 2025Article
- Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis.Circulation research · 2024Article
- Elevated apolipoprotein C3 augments diabetic kidney disease and associated atherosclerosis in type 2 diabetes.JCI insight · 2024Article
- Apolipoprotein C3: form begets function.Journal of lipid research · 2024Review
- Quartet of APOCs and the Different Roles They Play in Diabetes.Arteriosclerosis, thrombosis, and vascular biology · 2023Review
- Article
- FACI is a novel clathrin adaptor protein 2-binding protein that facilitates low-density lipoprotein endocytosis.Cell & bioscience · 2023Article
- A hepatokine derived from the ER protein CREBH promotes triglyceride metabolism by stimulating lipoprotein lipase activity.Science signaling · 2023Article
- Monocyte and macrophage foam cells in diabetes-accelerated atherosclerosis.Frontiers in cardiovascular medicine · 2023Review
- CREBH regulation of lipid metabolism through multifaceted functions that improve arteriosclerosis.Journal of diabetes investigation · 2022Article
- The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease.Arteriosclerosis, thrombosis, and vascular biology · 2022Review
- Recruiting a transcription factor in the liver to prevent atherosclerosis.The Journal of clinical investigation · 2021Article
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.