Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

Abstract

The liver is controlled by several metabolic hormones, including thyroid hormone, and characteristically displays high lysosomal activity as well as metabolic stress-triggered autophagy, which is stringently regulated by the levels of hormones and metabolites. Hepatic autophagy provides energy through catabolism of glucose, amino acids and free fatty acids for starved cells, facilitating the generation of new macromolecules and maintenance of the quantity and quality of cellular organelles, such as mitochondria. Dysregulation of autophagy and defective mitochondrial homeostasis contribute to hepatocyte injury and liver-related diseases, such as non-alcoholic fatty liver disease (NAFLD) and liver cancer. Thyroid hormones (TH) mediate several critical physiological processes including organ development, cell differentiation, metabolism and cell growth and maintenance. Accumulating evidence has revealed dysregulation of cellular TH activity as the underlying cause of several liver-related diseases, including alcoholic or non-alcoholic fatty liver disease and liver cancer. Data from epidemiologic, animal and clinical studies collectively support preventive functions of THs in liver-related diseases, highlighting the therapeutic potential of TH analogs. Elucidation of the molecular mechanisms and downstream targets of TH should thus facilitate the development of therapeutic strategies for a number of major public health issues. Here, we have reviewed recent studies focusing on the involvement of THs in hepatic homeostasis through induction of autophagy and their implications in liver-related diseases. Additionally, the potential underlying molecular pathways and therapeutic applications of THs in NAFLD and HCC are discussed.

Importance of thyroid-stimulating hormone levels in liver disease

“…The thyroid gland is closely connected to the liver. Thyroid hormones regulate the basal metabolic rate of hepatocytes, and dysthyroidism can cause altered bilirubin metabolism and hepatic circulation [1,2].…”

Peer Review #2 of "Nicotinamide riboside exerts protective effect against aging-induced NAFLD-like hepatic dysfunction in mice (v0.1)"

“…Physiological changes characterize aging may trigger the development of components of the metabolic disturbance. For example, the functional decrease in the lysosomal degradative pathway of autophagy appears to be remarkable in aged individual, which may encourage lipid accumulation in the liver (Martinez-Lopez and Athonvarangkul, 2015;Chi and Tsai, 2019). Furthermore, the level of oxidative stress, inflammation and DNA damage increase with aging, and these excessive elevations have also been implicated as mediators of NAFLD pathogenesis.…”

The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells

“…Overall, these results partly unveil the role and applicability of TSH/T4 in liver cancer treatment. Notably, the oncogenic role of thyroid hormones (not TSH/TSHR) in HCC is still under debate [115,116].…”