cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Min, Ae-Kyung; Jeong, Ji Yun; Y, Go; Choi, Youn‐Hee; Kim, Y.-D.; Lee, I.-K.; Park, K.-G.

doi:10.1007/s00125-012-2771-2

Cited by 20 publications

(18 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Certainly, adenoviral overexpression of pCREB3L3 in the livers of Ldlr -/- Creb3l3 -/- mice reduced nSREBP-1 and nSEEBP-2 protein expression (Figure 6B), indicating that in Ldlr -/- mice, SREBP cleavage was regulated by existence of pCREB3L3, rather than Insigs. It was reported that CREB3L3 suppresses LXRα-induced Srebf-1c expression by inhibiting LXRα binding to Srebf-1c promoter ( Min et al, 2013 ); however, in our data settings, Ldlr -/- TgCREB3L3 mice exhibited no changes in Srebf1c and its target genes.…”

Section: Discussioncontrasting

confidence: 86%

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Shimano

Nakagawa

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

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...

show abstract

Section: Discussioncontrasting

confidence: 86%

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Shimano

Nakagawa

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Increased ATGL and CPT I expression levels induced by fenofibrate have been reported in several studies [25][26][27]. Studies also indicated that fenofibrate induced mRNA expression of the enzymes involved in fatty acid oxidation in a variety of species [28,29]. ATGL is a rate-limiting lipolytic enzyme, which initiates hydrolysis of triglyceride and produces diacylglycerol and fatty acids [30].…”

Section: Discussionmentioning

confidence: 92%

Dietary Fenofibrate Reduces Hepatic Lipid Deposition by Regulating Lipid Metabolism in Yellow Catfish Pelteobagrus fulvidraco Exposed to Waterborne Zn

Zheng

Luo

et al. 2015

Lipids

View full text Add to dashboard Cite

Fenofibrate is known to possess lipid-lowering effects by regulation of gene transcription involved in lipid metabolism. Waterborne Zn exposure induces lipid deposition in yellow catfish Pelteobagrus fulvidraco. Thus, the present working hypothesis is that dietary fenofibrate addition will reduce hepatic lipids in yellow catfish exposed to waterborne Zn. To this end, juvenile yellow catfish were exposed to 0.04 (control), 0.35 mg/L waterborne Zn, 0.15% dietary fenofibrate, and 0.35 mg Zn/l + 0.15% dietary fenofibrate for 8 weeks. Growth performance, lipid deposition and metabolism in the liver were determined. Dietary fenofibrate promoted growth performance and reduced hepatic lipid content of yellow catfish exposed to waterborne Zn. However, these effects did not appear in fish in normal water. The lipid-lowering effect of fenofibrate on fish exposed to waterborne Zn was associated with increased lipolysis, as indicated by increased CPT I activities and expression of lipolytic genes PPARα, CPT IA, ATGL and HSL, and with reduced lipogenesis as indicated by reduced activities of G6PD, 6PGD, ME and ICDH. Dietary fenofibrate significantly increased mRNA levels of FAS, LPL and ACCα, but reduced mRNA levels of ACCβ and PPARγ in fish exposed to waterborne Zn. Pearson correlations between transcriptional factors expression, and activities and expression of several enzymes were observed, indicating that changes at the molecular and enzymatic levels may underlie the patterns of lipid metabolism and accordingly affect hepatic fat storage. Taken together, our results suggest that the lipid-lowering effect of fenofibrate was attributed, in part, to the down-regulation of lipogenesis and up-regulation of fatty acid oxidation.

show abstract

“…Total TG levels in liver were analyzed using Infinity reagents (Thermo DMA, Louisville, CO, USA), according to the manufacturer's protocol, as mentioned previously [21,22]. Serum TG levels were measured using a commercially available determination kits (Sigma-Aldrich).…”

Section: Measurement Of Hepatic and Serum Tg Contentsmentioning

confidence: 99%

“…For hematoxylin and eosin (H & E) staining, liver tissue samples were fixed with 4% paraformaldehyde and embedded with paraffin, as described previously [21,22]. Liver sections (4-5 μm) were performed with H & E staining according to the standard procedures.…”

Section: Histological Analysismentioning

confidence: 99%

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

Kim

Lee

Hwang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Alcohol consumption exacerbates alcoholic liver disease by attenuating the activity of AMP-activated protein kinase (AMPK). AMPK is activated by fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, and inhibited by direct interaction with cereblon (CRBN), a component of an E3 ubiquitin ligase complex. Based on these preliminary findings, we investigated that CRBN would be up-regulated in the liver by alcohol consumption and that CRBN deficiency would ameliorate hepatic steatosis and pro-inflammatory responses in alcohol-fed mice by increasing AMPK activity. Wild-type, CRBN and PPARα null mice were fed an alcohol-containing liquid diet and administered with fenofibrate. Gene expression profiles and metabolic changes were measured in the liver and blood of these mice. Expression of CRBN, cytochrome P450 2E1 (CYP2E1), lipogenic genes, pro-inflammatory cytokines, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were increased in the Lieber-DeCarli alcohol-challenged mice. Fenofibrate attenuated the induction of CRBN and reduced hepatic steatosis and pro-inflammatory markers in these mice. Ablation of the gene encoding CRBN produced the same effect as fenofibrate. The increase in CRBN gene expression by alcohol and the reduction of CRBN expression by fenofibrate were negated in PPARα null mice. Fenofibrate increased the recruitment of PPARα on CRBN gene promoter in WT mice but not in PPARα null mice. Silencing of AMPK prevented the beneficial effects of fenofibrate. These results demonstrate that activation of PPARα by fenofibrate alleviates alcohol-induced hepatic steatosis and inflammation by reducing the inhibition of AMPK by CRBN. CRBN is a potential therapeutic target for the alcoholic liver disease.

show abstract

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Cited by 20 publications

References 48 publications

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Dietary Fenofibrate Reduces Hepatic Lipid Deposition by Regulating Lipid Metabolism in Yellow Catfish Pelteobagrus fulvidraco Exposed to Waterborne Zn

Inhibition of cereblon by fenofibrate ameliorates alcoholic liver disease by enhancing AMPK

Contact Info

Product

Resources

About