Growth Hormone Signaling in Liver Diseases: Therapeutic Potentials and Controversies

Abstract

Growth hormone (GH) and downstream insulin-like growth factor 1 (IGF1) signaling mediate growth and metabolism. GH deficiency causes short stature or dwarfism, and excess GH causes acromegaly. Although the association of GH/IGF1 signaling with liver diseases has been suggested previously, current studies are controversial and the functional roles of GH/IGF1 signaling are still undefined. GH supplementation therapy showed promising therapeutic effects in some patients, such as non-alcoholic fatty liver disease, but inhibition of GH signaling may be beneficial for other liver diseases, such as hepatocellular carcinoma. The functional roles of GH/IGF1 signaling and the effects of agonists/antagonists targeting this signaling may differ depending on the liver injury or animal models. This review summarizes current controversial studies of GH/IGF1 signaling in liver diseases and discusses therapeutic potentials of GH therapy.

Plasma Growth Hormone Pulses Induce Male-biased Pulsatile Chromatin Opening and Epigenetic Regulation in Adult Mouse Liver

“…The gene targets of each sex-biased DHS set were enriched for distinct but partially overlapping Gene Ontology (GO) Biological Processes, as determined by GREAT analysis. Top enriched GO terms common to both dynamic and static male-biased DHS included lipid metabolic process and steroid metabolic process, consistent with the major role that GH plays in the male-prevalence of fatty liver development and liver metabolic disease [3–5]. Unique enriched terms for dynamic male-biased DHS included cell adhesion, gland development and hepaticobiliary development, whereas gene targets of static male-biased DHS were uniquely enriched for cellular response to glucocorticoid stimulus and EGF receptor signaling, among others (Fig.…”

“… A. Distribution of static and dynamic DHS in the defined classes of enhancer DHS, weak enhancer DHS, insulator DHS and promoter DHS, based on histone mark patterns [5]. B. Chromatin state distributions in male mouse liver of dynamic and static male-biased DHS, based on the 14 chromatin state model developed from the combination of six active and repressive histone marks and DHS, which segment the mouse genome into inactive, bivalent, enhancer-like, promoter-like, or transcribed-like states [6].…”

“…1C). Key results : Overall, 92-96% of dynamic and static male-biased DHS were classified as enhancers, with a larger fraction being weak enhancers [5] in the case of static male-biased DHS. Promoter DHS and insulator DHS comprised the balance of each male-biased DHS set (2-5% each) ( A ).…”

“…Growth hormone (GH) regulates hepatic expression of enzymes and transporters that play critical roles in lipid metabolism and in the detoxification of many drugs and other lipophilic foreign chemicals [1, 2]. Dysregulation of hepatic GH signaling can lead to liver metabolic disorders, including the development of fatty liver disease and non-alcoholic steatohepatitis, with males more susceptible than females, as seen in both mice and humans [3–5]. Correspondingly, GH regulates many liver-expressed genes in a sex-dependent manner, enabling each sex to meet its specific metabolic and hormonal requirements [6].…”

Plasma growth hormone pulses induce male-biased pulsatile chromatin opening and epigenetic regulation in adult mouse liver

“…Growth hormone (GH) regulates hepatic expression of enzymes and transporters that play critical roles in lipid metabolism ( Vázquez-Borrego et al, 2021 ) and in the detoxification of many drugs and other lipophilic foreign chemicals ( Waxman and Holloway, 2009 ). Dysregulation of hepatic GH signaling can lead to liver metabolic disorders, including the development of fatty liver disease and non-alcoholic steatohepatitis, with males more susceptible than females, as seen in both mice and humans ( Dichtel et al, 2022 ; Kaltenecker et al, 2019 ; Oxley et al, 2023 ). Correspondingly, GH regulates many liver-expressed genes in a sex-dependent manner, enabling each sex to meet its specific metabolic and hormonal requirements ( Wauthier et al, 2010 ).…”