Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system.
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.
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Yoshimi
Y
Nakagawa
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Fusaka
F
Oikawa
Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Seiya
S
Mizuno
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Hiroshi
H
Ohno
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Yuka
Y
Yagishita
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Aoi
A
Satoh
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Yoshinori
Y
Osaki
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Kenta
K
Takei
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Takuya
T
Kikuchi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Song-Iee
SI
Han
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Takashi
T
Matsuzaka
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Hitoshi
H
Iwasaki
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Kazuto
K
Kobayashi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Shigeru
S
Yatoh
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Naoya
N
Yahagi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Masaaki
M
Isaka
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Hiroaki
H
Suzuki
Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Niigata 951-8510, Japan.
Hirohito
H
Sone
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.|Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.|Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Satoru
S
Takahashi
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.
Nobuhiro
N
Yamada
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, JAPAN.|International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Hitoshi
H
Shimano
D000818:Animals; D064113:CRISPR-Cas Systems / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism; D002796:Choline Deficiency; D017362:Cyclic AMP Response Element-Binding Protein / Q000172:deficiency / Q000235:genetics*; D005260:Female; D006520:Hepatitis, Animal / Q000209:etiology* / Q000378:metabolism; D006949:Hyperlipidemias / Q000209:etiology* / Q000378:metabolism / Q000662:veterinary; D007328:Insulin / Q000097:blood; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation
C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D002784:Cholesterol; D008715:Methionine