Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr ^−/− Mice

Jul 16, 2016Arteriosclerosis, thrombosis, and vascular biology

Losing the CREBH Protein Speeds Up Diet-Related Artery Disease in Mice Without LDL Receptors

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Abstract

CREBH deletion in double knockout mice increased very low-density lipoprotein-associated triglyceride and cholesterol levels.

Impairment of lipoprotein lipase-mediated triglyceride clearance was observed in CREBH-deficient mice.
High-density lipoprotein cholesterol levels decreased in the absence of CREBH, linked to reduced liver production of apoA-I.
CREBH directly activated the transcription of the Apoa1 gene.
Ldlr(-/-) Creb3l3(-/-) mice exhibited a worsened atherogenic lipid profile.
These mice developed significantly more atherosclerotic lesions in the aortas compared to Ldlr(-/-) mice.

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OBJECTIVE: Liver-enriched transcription factor cAMP-responsive element-binding protein H (CREBH) regulates plasma triglyceride clearance by inducing lipoprotein lipase cofactors, such as apolipoprotein A-IV (apoA-IV), apoA-V, and apoC-II. CREBH also regulates apoA-I transcription. This study aims to determine whether CREBH has a role in lipoprotein metabolism and development of atherosclerosis.

APPROACH AND RESULTS: CREBH-deficient Creb3l3(-/-) mice were bred with Ldlr(-/-) mice creating Ldlr(-/-) Creb3l3(-/-) double knockout mice. Mice were fed on a high-fat and high-sucrose Western diet for 20 weeks. We showed that CREBH deletion in Ldlr(-/-) mice increased very low-density lipoprotein-associated triglyceride and cholesterol levels, consistent with the impairment of lipoprotein lipase-mediated triglyceride clearance in these mice. In contrast, high-density lipoprotein cholesterol levels were decreased in CREBH-deficient mice, which was associated with decreased production of apoA-I from the liver. The results indicate that CREBH directly activated Apoa1 gene transcription. Accompanied by the worsened atherogenic lipid profile, Ldlr(-/-) Creb3l3(-/-) mice developed significantly more atherosclerotic lesions in the aortas than Ldlr(-/-) mice.

CONCLUSIONS: We identified CREBH as an important regulator of lipoprotein metabolism and suggest that increasing hepatic CREBH activity may be a novel strategy for prevention and treatment of atherosclerosis.

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Loss of Transcription Factor CREBH Accelerates Diet-Induced Atherosclerosis in Ldlr ^−/− Mice

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