title: Endoplasmic Reticulum Stress May Play a Pivotal Role in Lipid Metabolic Disorders in a Novel Mouse Model of Subclinical Hypothyroidism.
abstract: Subclinical hypothyroidism (SCH) is becoming a global health problem due to its increasing prevalence and potential deleterious effects. However, the molecular mechanisms underlying the lipid metabolic disorders in SCH have not been fully clarified. Additionally, progress in elucidating the exact pathogenesis of SCH has been hampered by the lack of optimized mouse models. Methimazole (MMI) was applied to construct a noninvasive SCH mouse model. Eight-week-old C57BL/6 mice were administrated MMI through the drinking water. After 12 weeks, the MMI-treated mice showed the diagnostic criteria for SCH: increased serum thyrotropin (TSH) levels with constant thyroid hormone levels that persisted for approximately 8 weeks. Notably, SCH mice presented evident lipid metabolic disturbances, including dyslipidemia and hepatic lipid accumulation. Further analysis showed that hepatic endoplasmic reticulum stress (ER stress) was induced in the SCH mice or by the elevation of TSH in vitro, likely via the IRE1α/XBP-1 pathway. Interestingly, when we used 4-phenyl butyric acid to repress ER stress in SCH mice for 4 weeks, dyslipidemia and hepatic lipid accumulation were both significantly alleviated. Our findings indicate that an optimized SCH mouse model could be established using MMI, and ER stress may play a pivotal role in the lipid metabolic abnormalities in SCH.
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Experimental Animal Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Shuyan
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Laicheng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Bo
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.
authors.forename: Kunpeng
authors.initials: K
authors.lastname: Wu
authors.affiliation: Jinan central hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.|Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan, Shandong, 250021, China.|Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, Shandong, 250021, China.|Scientific Center, Shandong Provincial Hospital affiliated to Shandong University, Jinan, Shandong, 250021, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced* / Q000150:complications; D052439:Lipid Metabolism Disorders / Q000097:blood* / Q000188:drug therapy; D008713:Methimazole / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000494:pharmacology; D013963:Thyroid Hormones / Q000097:blood*; D013972:Thyrotropin / Q000097:blood*
chemical_list: D010654:Phenylbutyrates; D013963:Thyroid Hormones; D008713:Methimazole; C075773:4-phenylbutyric acid; D013972:Thyrotropin