Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms

Abstract

<p id="d13005836e332">Cross-sectional studies have demonstrated that hypothyroidism is an independent risk factor for nonalcoholic fatty liver disease (NAFLD). However, the pathogenesis of hypothyroidism-induced NAFLD has yet to be characterized. Here we found that hypothyroidism induces NAFLD through a pleiotropic effect of thyroid hormones (THs) on insulin secretion and adrenergic stimulation of lipolysis in adipose tissue. A mild reduction in serum TH levels impairs insulin secretion, leading to impaired suppression of lipolysis and increased shuttling of fatty acids to the liver, where they induce NAFLD. Surprisingly, a severe reduction in serum TH levels protects against the development of NAFLD through a constitutive suppression of lipolysis. These results shed light on mechanisms that either induce or protect against NAFLD in hypothyroidism. </p><p class="first" id="d13005836e335">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. </p>