ArticleProceedings of the National Academy of Sciences of the United States of America2017
Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 75 citations in OpenAlex.
- Association between thyroid function and metabolic associated fatty liver disease: a systemic review and meta-analysis.Frontiers in endocrinology · 2025Pooled it
- The HEAT Repeat Protein MROH1 Deficiency Leads to Reduced Circulating Thyroid Hormone Levels in Mice.Endocrinology, diabetes & metabolism · 2026Article
- Exercise-Induced Hepatic Mitochondrial Reprogramming Across Muscle-Gut-Thyroid Axes in MASLD/MASH.International journal of molecular sciences · 2026Review
- Overnutrition in mice impairs thyroid hormone biosynthesis and utilization, causing hypothyroidism, despite remarkable thyroidal adaptations.The Journal of clinical investigation · 2026Article
- Correlation Between the Thyroid Hormone Levels and Type 2 Diabetes Mellitus in Non-Alcoholic Fatty Liver Disease.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Article
- Association of thyroid function and thyroid hormone sensitivity with all-cause and cardiovascular mortality in euthyroid patients with MASLD.Clinical and experimental hepatology · 2025Article
- Methionine Supplementation Benefits Lipogenesis in Goat Intramuscular Adipocytes, Likely by Inhibiting the Expression ofAnimals : an open access journal from MDPI · 2025Article
- Thyroid dysfunction in MASLD: Results of a nationwide study.JHEP reports : innovation in hepatology · 2025Article
- Association of Sensitivity to Thyroid Hormones and Non-Alcoholic Fatty Liver Disease and the Severity of Liver Fibrosis in Euthyroid Adults: A Retrospective Study.Diabetes, metabolic syndrome and obesity : targets and therapy · 2025Article
- Correlation analysis of thyroid function and vitamin D levels in patients with type 2 diabetes.Frontiers in endocrinology · 2025Article
- The Downregulation of the Liver Lipid Metabolism Induced by Hypothyroidism in Male Mice: Metabolic Flexibility Favors Compensatory Mechanisms in White Adipose Tissue.International journal of molecular sciences · 2024Article
- Impact of methimazole-induced hypothyroidism on postnatal swine.Physiological reports · 2024Article
- Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) and Thyroid Function in Childhood Obesity: A Vicious Circle?Children (Basel, Switzerland) · 2024Review
- Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice.Scientific reports · 2024Article
- Review
- Conferring liver selectivity to a thyromimetic using a novel nanoparticle increases therapeutic efficacy in a diet-induced obesity animal model.PNAS nexus · 2023Article
- Low-Normal Thyroid Function Is Not Associated with Either Non-Alcoholic Fatty Liver Disease or with Metabolic Dysfunction-Associated Fatty Liver Disease.Life (Basel, Switzerland) · 2023Article
- The nonlinear relationship between thyroid function parameters and metabolic dysfunction-associated fatty liver disease.Frontiers in endocrinology · 2023Article
- Association between Thyroid Hormones and Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis in Obese Individuals Undergoing Bariatric Surgery.Middle East journal of digestive diseases · 2022Article
- Low Bone Turnover Due to Hypothyroidism or Anti-Resorptive Treatment Does Not Affect Whole-Body Glucose Homeostasis in Male Mice.Journal of personalized medicine · 2022Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.
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