CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

Nakagawa, Yoshimi; Satoh, Aoi; Tezuka, Hitomi; Han, Song‐iee; Takei, Kenta; Iwasaki, Hitoshi; Yatoh, Shigeru; Yahagi, Naoya; Suzuki, Hiroaki; Iwasaki, Yoshinobu; Sone, Hirohito; Matsuzaka, Takashi; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1038/srep39182

Cited by 49 publications

(52 citation statements)

References 44 publications

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“…Conversely, hepatic nuclear CREB3L3 overexpression strikingly attenuated WD-induced hyperlipidemia and atherosclerosis progression in Ldlr -/- mice. As many pieces of literature including ours and the present work confirmed that the primary role of CREB3L3 is regulation of TG metabolism ( Lee et al, 2011, Nakagawa et al, 2016a, Nakagawa et al, 2016b, Nakagawa et al, 2014, Satoh et al, 2020 ), TG per se has been questioned as the major atherosclerosis risk factor, highlighting the cholesterol-related or more comprehensive mechanisms for potential mechanisms of anti-atherogenic effects of CREB3L3.…”

Section: Discussionsupporting

confidence: 69%

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Shimano

Nakagawa

Wang

et al. 2020

Preprint

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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...

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Section: Discussionsupporting

confidence: 69%

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Shimano

Nakagawa

Wang

et al. 2020

Preprint

Self Cite

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“…Of 44 transcription factors previously shown to be differentially expressed between proximal vs distal enterocytes 11 , only one associated with proximal identity, cAMP responsive element binding protein 3 like 3 (Creb3l3), was upregulated in SBR (0.46 average log fold increase in SBR, p<0.0001). Creb3l3 is a master regulator of lipid metabolism 29 , fitting with increased lipid metabolism after SBR. An additional transcription factor, Kruppel-like factor 4 (Klf4) was also increased in SBR (0.26 average log fold increase in SBR, p<0.001).…”

Section: Proximal Si Transcription Factor Creb3l3 Shows Stable Upregumentioning

confidence: 99%

Single-Cell Analysis Reveals Regional Reprogramming during Adaptation to Massive Small Bowel Resection in Mice

Seiler

Waye

Kong

et al. 2019

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Synopsis:Here, single-cell RNA sequencing reveals interactions between the retinoid metabolism pathway and 'regional reprogramming' of distal small intestinal epithelium to a proximal identity following proximal small bowel resection. This provides novel insight into physiological adaptation to short gut syndrome. Abstract:Background & Aims: The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or 'adapt'; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS.Methods: Single-cell RNA-sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs. sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH.Results: Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR.Conclusions: Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes-conceivably by engaging the retinoid metabolism pathway-merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS.

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“…In addition, transcription factor PPARα was likely activated in the liver of A. davidianus after prolonged fasting by Upstream Regulator Analysis in IPA. The activated PPARα by fasting promoted the expression of fatty acid oxidation and ketogenesis-related genes in synergy with other fastingrelated transcription factors, such as CREB3L3 (Nakagawa et al, 2016), p300 (Zhang et al, 2016), and PGC-1α (Rodgers and Puigserver, 2007). These results indicate that the enhanced fatty acid oxidation is needed to provide energy for the A. davidianus after prolonged fasting and can also explain why A. davidianus can survive for long periods of food deprivation.…”

Section: Fatty Acid β-Oxidation and Ketogenesis Are Up-regulated Durimentioning

confidence: 79%

Differential Proteomic Analysis of Chinese Giant Salamander Liver in Response to Fasting

et al. 2020

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Chinese giant salamander Andrias davidianus has strong tolerance to starvation. Fasting triggers a complex array of adaptive metabolic responses, a process in which the liver plays a central role. Here, a high-throughput proteomic analysis was carried out on liver samples obtained from adult A. davidianus after 3, 7, and 11 months of fasting. As a result, the expression levels of 364 proteins were significantly changed in the fasted liver. Functional analysis demonstrated that the expression levels of key proteins involved in fatty acid oxidation, tricarboxylic acid cycle, gluconeogenesis, ketogenesis, amino acid oxidation, urea cycle, and antioxidant systems were increased in the fasted liver, especially at 7 and 11 months after fasting. In contrast, the expression levels of vital proteins involved in pentose phosphate pathway and protein synthesis were decreased after fasting. We also found that fasting not only activated fatty acid oxidation and ketogenesis-related transcription factors PPARA and PPARGC1A, but also activated gluconeogenesis-related transcription factors FOXO1, HNF4A, and KLF15. This study confirms the central role of lipid and acetyl-CoA metabolism in A. davidianus liver in response to fasting at the protein level and provides insights into the molecular mechanisms underlying the metabolic response of A. davidianus liver to fasting.

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CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα

Cited by 49 publications

References 44 publications

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition

Single-Cell Analysis Reveals Regional Reprogramming during Adaptation to Massive Small Bowel Resection in Mice

Differential Proteomic Analysis of Chinese Giant Salamander Liver in Response to Fasting

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