Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Abstract

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.

Making the Best of a Competition: the CREB3L3–SREBP Axis in Arteriosclerosis

“…The results of this study fit well with previous work showing that hepatic and intestinal CREB3L3 contribute to cholesterol metabolism. 10,11,13 Consistent with a previous report that CREB3L3 controls liver X receptor signaling, 17 Nakagawa et al 15 also confirmed decreased liver X receptor signaling and an increased lipid content in the intestines of LDLR -/-CREB3L3 -/mice. However, in contrast to previously published findings showing that the atherogenic phenotype of CREB3L3 mice is dependent on plasma FGF21, 5,11,18 in the current study the deficiency of FGF21 in LDLR -/-Tg CREB3L3 mice did not negate the amelioration of arteriosclerosis, suggesting that FGF21 is not the sole contributor to the anti-arteriosclerosis effects of CREB3L3.…”

“…In summary, Nakagawa et al 15 have enhanced our understanding of the complex regulation of lipid metabolism, showing a functional competition between CREB3L3 and SREBP and its consequences to the progress of arteriosclerosis. Therapeutic strategies designed to modulate CREB3L3 and/or SREBP cleavage, trafficking, or subcellular localization might be beneficial in the treatment of hyperlipidemia, arteriosclerosis, and obesity-associated metabolic diseases.…”

CREBH Systemically Regulates Lipid Metabolism by Modulating and Integrating Cellular Functions

“…CREBH overexpression in LDLR KO mice increases apolipoprotein-related genes, such as Apoa1, Apoa4, Apoa5, and Apoc2, which stimulates LPL-mediated triglyceride clearance (Figures 2 and 3) [40,52]. Conversely, deficiency of CREBH in LDLR KO mice reduces the expression of these genes, thereby inducing hypertriglyceridemia [40,52]. FGF21 deficiency in ApoE KO mice results in severe atherogenic phenotypes [53], but administering FGF21 to these ApoE KO mice ameliorates atherosclerosis [54].…”

“…In contrast, CREBH overexpression in the liver reduces plasma triglyceride levels. CREBH overexpression in LDLR KO mice increases apolipoprotein-related genes, such as Apoa1 , Apoa4 , Apoa5 , and Apoc2 , which stimulates LPL-mediated triglyceride clearance ( Figure 2 and Figure 3 ) [ 40 , 52 ]. Conversely, deficiency of CREBH in LDLR KO mice reduces the expression of these genes, thereby inducing hypertriglyceridemia [ 40 , 52 ].…”

“…Thus, the exacerbation of atherosclerosis in CREBH KO mice might contribute to the dysfunction of the CREBH-FGF21 pathway. However, the overexpression of CREBH in FGF21 KO:LDLR KO mice improves atherosclerosis [ 52 ], suggesting that the contribution of FGF21 to the CREBH-mediated improvement of atherosclerosis is not substantial. Nonetheless, the contribution of FGF21 to arteriosclerosis is important.…”