Endoplasmic reticulum stress induces up-regulation of hepatic β-Klotho expression through ATF4 signaling pathway.
Fibroblast growth factor 21 (FGF21) plays critical roles in regulating glucose and lipid metabolism. β-Klotho is the co-receptor for mediating FGF21 signaling, and the mRNA levels of this receptor are increased in the liver of human subjects with obesity. However, the molecular mechanisms underlying the regulation of β-klotho expression remain poorly defined. Here, we report that elevation of β-klotho protein expression in diet-induced obese mice and human patients is associated with increased endoplasmic reticulum (ER) stress. In vivo study indicates that administration of the ER stressor tunicamycin in mice led to increased expression of β-klotho in the liver. In addition, we show that ER stress is sufficient to potentiate FGF21 signaling in HepG2 cell and ATF4 signaling pathway is essential for mediating the effect of ER stress on β-klotho expression. These findings demonstrate a link of ER stress with up-regulation of hepatic β-klotho expression and the molecular mechanism underlying ER stress-regulated FGF21 signaling.
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Kun
K
Dong
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Huating
H
Li
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Mingliang
M
Zhang
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Shan
S
Jiang
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Shuqin
S
Chen
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Jian
J
Zhou
Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
Zhi
Z
Dai
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Qichen
Q
Fang
Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. Electronic address: wpjia@sjtu.edu.cn.
Weiping
W
Jia
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000633:toxicity; D015854:Up-Regulation / Q000235:genetics
C497109:ATF4 protein, human; C081452:Atf4 protein, mouse; C538995:KLB protein, human; C418622:Klb protein, mouse; D008565:Membrane Proteins; C414620:fibroblast growth factor 21; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins
Endoplasmic reticulum stress; Fibroblast growth factor 21; Non-alcoholic fatty liver disease; β-Klotho