Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms
| Autor: | Vishwa Deep Dixit, Rachel J. Perry, Rebecca L. Cardone, Richard G. Kibbey, Rachel R. Kaspari, Giuseppe Ferrandino, Olga Spadaro, Andrea Reyna-Neyra, Nancy Carrasco, Gerald I. Shulman |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine endocrine system medicine.medical_specialty endocrine system diseases Lipolysis medicine.medical_treatment Adipose tissue Biology digestive system 03 medical and health sciences chemistry.chemical_compound Insulin resistance Hypothyroidism Non-alcoholic Fatty Liver Disease Insulin-Secreting Cells Internal medicine Insulin Secretion Nonalcoholic fatty liver disease medicine Animals Insulin Obesity Mice Knockout Multidisciplinary Symporters Triglyceride nutritional and metabolic diseases Lipid Metabolism medicine.disease digestive system diseases Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology Adipose Tissue Liver PNAS Plus chemistry Lipogenesis Insulin Resistance Hormone |
| Zdroj: | Proceedings of the National Academy of Sciences. 114 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1707797114 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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