Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism

被引：55

作者：

Sasako, Takayoshi ^{[1
,2
,3
,4
,5
]}

Ohsugi, Mitsuru ^{[1
]}

Kubota, Naoto ^{[1
,2
,6
]}

Itoh, Shinsuke ^{[1
,7
]}

Okazaki, Yukiko ^{[1
,3
]}

Terai, Ai ^{[1
,3
]}

Kubota, Tetsuya ^{[1
,8
,9
]}

Yamashita, Satoshi ^{[10
]}

Nakatsukasa, Kunio ^{[11
,12
]}

Kamura, Takumi ^{[11
]}

Iwayama, Kaito ^{[13
]}

Tokuyama, Kumpei ^{[13
]}

Kiyonari, Hiroshi ^{[14
,15
]}

Furuta, Yasuhide ^{[14
,15
]}

Shibahara, Junji ^{[16
]}

Fukayama, Masashi ^{[16
]}

Enooku, Kenichiro ^{[17
]}

Okushin, Kazuya ^{[17
]}

Tsutsumi, Takeya ^{[18
]}

Tateishi, Ryosuke ^{[17
]}

Tobe, Kazuyuki ^{[19
]}

Asahara, Hiroshi ^{[10
]}

Koike, Kazuhiko ^{[17
]}

Kadowaki, Takashi ^{[1
,2
,20
,21
]}

Ueki, Kohjiro ^{[1
,2
,3
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo 1138655, Japan

[2] Univ Tokyo, TSBMI, Tokyo 1138655, Japan

[3] Natl Ctr Global Hlth & Med, Diabet Res Ctr, Dept Mol Diabet Med, Tokyo 1628655, Japan

[4] Univ Tokyo, Div Hlth Serv Promot, Tokyo 1130033, Japan

[5] Univ Tokyo, Grad Sch Med, Dept Mol Sci Diabet, Tokyo 1138655, Japan

[6] Univ Tokyo, Univ Tokyo Hosp, Dept Clin Nutr Therapy, Tokyo 113865, Japan

[7] Kowa Co Ltd, Nagoya, Aichi 4600003, Japan

[8] Natl Inst Hlth & Nutr, Clin Nutr Program, Tokyo 1628636, Japan

[9] Toho Univ, Ohashi Med Ctr, Div Cardiovasc Med, Tokyo 1438541, Japan

[10] Tokyo Med & Dent Univ, Dept Syst BioMed, Tokyo 1138510, Japan

[11] Nagoya Univ, Grad Sch Sci, Div Biol Sci, Nagoya, Aichi 4648601, Japan

[12] Nagoya City Univ, Grad Sch Nat Sci, Nagoya, Aichi 4648601, Japan

[13] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan

[14] RIKEN, Ctr Life Sci Technol, Anim Resource Dev Unit, Kobe, Hyogo 6500047, Japan

[15] RIKEN, Ctr Life Sci Technol, Genet Engn Team, Kobe, Hyogo 6500047, Japan

[16] Univ Tokyo, Grad Sch Med, Dept Pathol, Tokyo 1138655, Japan

[17] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Tokyo 1138655, Japan

[18] Univ Tokyo, Grad Sch Med, Dept Infect Dis, Tokyo 1138655, Japan

[19] Toyama Univ, Grad Sch Med & Pharmaceut Sci Res, Dept Internal Med 1, Toyama 9308555, Japan

[20] Univ Tokyo, Grad Sch Med, Dept Prevent Diabet & Lifestyle Related Dis, Tokyo 1138655, Japan

[21] Teikyo Univ, Mizonokuchi Hosp, Dept Metab & Nutr, Fac Med, Tokyo 2138507, Japan

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

ENDOPLASMIC-RETICULUM STRESS; BOX-BINDING PROTEIN-1; INSULIN-RESISTANCE; O-MANNOSYLATION; LINKS OBESITY; BETA-CELLS; EXPRESSION; LIVER; ACTIVATION; CHAPERONES;

D O I：

10.1038/s41467-019-08591-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.

引用

页数：16

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