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大学・研究所にある論文を検索できる 「Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Nakagawa, Yoshimi Wang, Yunong Han, Song-iee Okuda, Kanako Oishi, Asayo Yagishita, Yuka Kumagai, Kae Ohno, Hiroshi Osaki, Yoshinori Mizunoe, Yuhei Araki, Masaya Murayama, Yuki Iwasaki, Hitoshi Konishi, Morichika Itoh, Nobuyuki Matsuzaka, Takashi Sone, Hirohito Yamada, Nobuhiro Shimano, Hitoshi 京都大学 DOI:10.1016/j.jcmgh.2020.11.004

2021

概要

Background and 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 upregulates 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 (SREBP-INSIG1) 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.

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