Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System

Abstract

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics.

Cell type‐specific actions of thyroid hormones in nonalcoholic steatohepatitis and liver fibrosis

“…To further dissect the functional relevance of TRα on HSCs during inflammation and fibrogenesis the authors employed single cell RNA sequencing (scRNA‐seq) of TRα −/− mouse embryonic fibroblasts (MEFs) and investigated MCD diet‐induced NASH and liver fibrosis in TRα −/− mice 10 . As anticipated, scRNA‐seq revealed that TRα is involved in inflammatory and many energy dependent signalling pathways including glucose, lipid and protein metabolism 5,10 . Activation of HSCs and transdifferentiation into ECM‐producing myofibroblasts requires an energy‐intensive metabolic reprogramming—thus, this study highlights the relevance of local and cell type‐specific TH activities 5,12,13 .…”

“…gluconeogenesis, glycolysis, glycogen synthesis, lipogenesis, lipolysis, uptake and ß-oxidation of FFA). 5 Approximately 80% of the total liver tissue is occupied by parenchymal liver cells (i.e. hepatocytes).…”

“…4 Among those, thyroid hormones (THs) are key players of systemic and local energy metabolism-thus, representing critical regulators in homeostasis as well as modifiers of metabolic injury and inflammation. 5,6 Recent efficacy data from phase 3 clinical trials with the TH agonist resmetirom in patients with NASH demonstrated not only beneficial metabolic effects, but also improvement of NASH and fibrosis. 7 However, the exact role of THs modulating inflammatory processes during NASHprogression and fibrogenesis is less clear.…”

Resmetirom: Finally, the Light at the End of the NASH Tunnel?

“…Understanding the relationship between NASH and thyroid function in healthy states is critical for conceptualizing how hypothyroidism perturbs this relation [24,25]. In the liver, thyroid hormones (THs) regulate energy and metabolic homeostasis by modulating the export of lipids from the hepatocyte into the bile and the blood stream, as well as their oxidation and de novo lipogenesis [26].…”

Optimized Mass Spectrometry Detection of Thyroid Hormones and Polar Metabolites in Rodent Cerebrospinal Fluid

“…Few methods address these dual challenges of sample scarcity and low levels, leading to infrequent reports on CSF hormone levels [30]. A further advantage of using LC-MS to quantify TH in CSF is that it can be combined with global assessments of the metabolic state through targeted LC-MS metabolic profiling of central energy metabolism, a process dependent on TH during development and adulthood [8,23,27,[38][39][40][41]. Better detection and reporting of this key hormone in CSF requires a new and sensitive approach, which we describe here.…”