Correspondence; 29 ynaka@inm.u-toyama.ac.jp 30 and 31 hshimano@md.tsukuba.ac.jp 32 33 34 Summary 35CREB3L3 is a membrane-bound transcription factor to maintain lipid metabolism in the liver 36 and small intestine. CREB3L3 ablation in Ldlr −/− mice exacerbated hyperlipidemia with 37 remnant ApoB-containing lipoprotein accumulation, developing enhanced aortic atheroma 38 formation, whose extent was additive between liver-and intestine-specific deletion. 39
Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis 40 with amelioration of hyperlipidemia. CREB3L3 directly upregulates anti-atherogenic FGF21 41 and ApoA4, whereas antagonizes hepatic SREBP-mediated lipogenic and cholesterogenic 42 genes and regulates LXR-regulated genes involved in intestinal transport of cholesterol. 43 CREB3L3 deficiency accumulates nuclear SREBP proteins. Because both transcriptional 44 factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and 45 SREBPs on endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 46 competitively antagonizes SREBPs for ER-Golgi transport, resulting in ER retention and 47 proteolytic activation inhibition at Golgi, and vice versa. Collectively, due to this new 48 mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions, 49 CREB3L3 has multi-potent protective effects against atherosclerosis. 50 51 52 53 54cAMP responsive element-binding protein 3 like 3 (Creb3l3) is expressed only in 55 liver and intestinal cells (Lee et al. , 2011), where the CREB3L3 protein localizes in the 56 endoplasmic reticulum (ER) and is transported to the Golgi apparatus and nucleus (Lee et 57 al. , 2011, Omori et al. , 2001, Zhang et al. , 2006. Nuclear expression of the active form of 58 CREB3L3 in the nucleus is increased under fasting, consistent with the finding that Creb3l3 59 mRNA expression is higher during fasting than refeeding (Danno et al. , 2010). CREB3L3 60 reduces plasma triglyceride (TG) levels by increasing hepatic expression of apolipoprotein-61 encoding genes, such as apolipoprotein A4 (Apoa4), Apoa5, and Apoc2 (Lee et al. , 2011); 62 these activate blood lipoprotein lipase (LPL) activity. Creb3l3 −/− mice exhibit massive hepatic 63 lipid metabolite accumulation and significantly increased plasma TG levels, or nonalcoholic 64 steatohepatitis when fed an atherogenic high-fat diet (Luebke-Wheeler et al. , 2008). Apoa4 65 regulates HDL metabolism by activating lecithin-cholesterol acyltransferase, a key enzyme 66 involved in cholesterol transfer to newly synthesized HDL particles (Chen and Albers, 1985, 67 Steinmetz and Utermann, 1985), stimulating cholesterol efflux from macrophages (Fournier 68 et al. , 2000) and activating receptor-mediated uptake of HDL by hepatocytes (Steinmetz et 69 al. , 1990). Apoa4-overexpressed mice prevent atherosclerosis development (Cohen et al. , 70 1997, Duverger et al. , 1996, Ostos et al. , 2001. 71 CREB3L3 and peroxisome proliferator-activated receptor alpha (PPARα) 72...
