Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes

Nakagawa, Yoshimi; Satoh, Aoi; Yabe, Sachiko; Furusawa, Mika; Tokushige, Naoko; Tezuka, Hitomi; Mikami, Motoki; Iwata, Wakiko; Shingyouchi, Akiko; Matsuzaka, Takashi; Kiwata, Shiori; Fujimoto, Yuri; Shimizu, Hidehisa; Danno, Hirosuke; Yamamoto, Takashi; Ishii, Kiyo‐aki; Karasawa, Tadayoshi; Takeuchi, Yoshinori; Iwasaki, Hitoshi; Shimada, Masako; Kawakami, Yasushi; Urayama, Osamu; Sone, Hirohito; Takekoshi, Kazuhiro; Kobayashi, Kazuto; Yatoh, Shigeru; Takahashi, Akimitsu; Yahagi, Naoya; Suzuki, Hiroaki; Yamada, Nobuhiro; Shimano, Hitoshi

doi:10.1210/en.2014-1113

Cited by 57 publications

(125 citation statements)

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“…Plasma TG and glucose levels have been reported to be higher, with cholesterol and FGF21 levels reported lower, in Creb3l3 −/− mice compared to WT mice516. Plasma TG, cholesterol, and free fatty acid levels were significantly increased in LKO mice compared to floxed mice in both fasted and fed conditions (Fig.…”

Section: Resultsmentioning

confidence: 86%

Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system

Nakagawa

Oikawa

Mizuno

et al. 2016

Sci Rep

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cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice. While LKO mice as well as global KO mice developed hypertriglyceridemia, LKO mice exhibited hypercholesterolemia in contrast to hypocholesterolemia in global KO mice. LKO mice demonstrated up-regulation of hepatic Srebf2 and its corresponding target genes. No phenotypic differences were observed between IKO and floxed mice. Severe liver injury was observed in LKO mice fed a methionine-choline deficient diet, a model for non-alcoholic steatohepatitis. These results provide new evidence regarding the hepatic CREB3L3 role in plasma triglyceride metabolism and hepatic and intestinal CREB3L3 contributions to cholesterol metabolism.

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Section: Resultsmentioning

confidence: 86%

Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system

Nakagawa

Oikawa

Mizuno

et al. 2016

Sci Rep

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“…It was speculated that the position effects of the transgenic cassette inserted into the genome happened not to express ectopic CREBH expression in the liver. To confirm the effects of transgene in the liver, we determined Fgf21 expression, which is the target of CREBH [20], [21], in the liver. There was a trend to increase Fgf21 expression in CREBH Tg mice, but it was not significant (Supplementary Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…To generate CREBH Tg mice, cDNAs encoding the rat Pck1 promoter, active human CREBH (amino acids 1–320), and the 3′ polyadenylation signal of human growth hormone were microinjected into C57BL6J eggs [21]. Creb3l3 tm1.1Sad /J (CREBH null) mice [18] were purchased from The Jackson Laboratory (Bar Harbor, ME, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Translated CREBH protein localizes to the endoplasmic reticulum (ER) before transfer to the Golgi apparatus, where the transcriptionally active N-terminal region is cleaved prior to translocation to the nucleus [19]. CREBH and peroxisome proliferator activated receptor alpha (PPARα) synergistically activate hepatic fibroblast growth factor 21 ( Fgf21 ) expression and exert effects on energy metabolism through the modulation of plasma FGF21 levels [20], [21]. CREBH reduces plasma triglyceride (TG) levels by increasing hepatic gene expression of apolipoproteins such as apolipoprotein A-IV ( Apoa4 ), Apoa5 , and Apoc2 .…”

Section: Introductionmentioning

confidence: 99%

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Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression

Kikuchi

Orihara

Oikawa

et al. 2016

Molecular Metabolism

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ObjectiveThe transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown.MethodsTo investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions.ResultsPlasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann–Pick C1-like 1 (Npc1l1), a rate-limiting transporter mediating intestinal cholesterol absorption, was reduced in the small intestine of CREBH Tg mice. Adenosine triphosphate-binding cassette transporter A1 (Abca1), Abcg5/8, and scavenger receptor class B, member 1 (Srb1) expression levels were also reduced in CREBH Tg mice. Promoter assays revealed that CREBH directly regulates Npc1l1 expression. Conversely, CREBH null mice exhibited higher intestinal Npc1l1 expression, elevated plasma and hepatic cholesterol, and lower fecal output.ConclusionIntestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia.

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“…We and others have defined CREBH to be a stress-inducible transcriptional activator that is critically involved in inflammation and metabolism (12)(13)(14)(15)(16). Metabolic stress and acute liver injuries can induce CREBH cleavage, mediated by the site 1 protease (SP1) and site 2 protease (SP2), the same enzymes that process sterol regulatory element binding proteins upon the demands of lipid or sterol biosynthesis (12).…”

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confidence: 99%

Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism

Kim

Méndez

Chen

et al. 2015

Molecular and Cellular Biology

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dCyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylationmimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor ␣ (PPAR␣) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH.T he liver is the central metabolic organ that plays primary roles in regulating lipid and glucose homeostasis upon alterations of metabolic conditions (1). Under fasting conditions, the liver boosts metabolic pathways of energy utilization, and the energy source is shifted from carbohydrates to triglycerides to meet the demands of the energy supplies. The major changes in liver metabolic pathways upon fasting include (i) glycogen utilization and gluconeogenesis to increase blood glucose levels and (ii) the catalysis of triglycerides (TG) in adipose tissue or liver to fatty acids (FA) and glycerol when the glycogen in liver is depleted. The released FA are directly oxidized as an energy source or metabolized to ketone bodies by the liver to supply energy to the brain, while glycerol is converted into glucose by the liver (2). Defects in these metabolic pathways may cause hepatic steatosis and abnormal levels of glucose and lipids in the blood. Notably, prolonged fasting results in the rapid mobilization of fat and the abnormal accumulation of FA and TG in the liver, leading to hepatic steatosis (3).Transcriptional regulation plays a major role in controlling energy metabolism. Increasing evidence suggests that the regulation of transcription factors via posttranslational modifications, such as phosphorylation, ubiquitination, glycosylation, and acetylation, plays an important role in transcriptional activity as w...

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Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes

Cited by 57 publications

References 39 publications

Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system

Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system

Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression

Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism

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