Role of Glucocorticoids in Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Purpose of the Review To summarize published data on the association between glucocorticoids and metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on the possible pathophysiological links and related treatment considerations. Recent Findings Glucocorticoids, commonly used for managing many inflammatory and autoimmune diseases, may contribute to the development and progression of MASLD. Glucocorticoids may induce hyperglycemia and hyperinsulinemia, thus increasing systemic and hepatic insulin resistance, a hallmark of MASLD pathogenesis. Furthermore, glucocorticoids increase adipose tissue lipolysis, and hepatic de novo lipogenesis and decrease hepatic fatty acid β-oxidation, thus promoting MASLD development. Preclinical evidence also suggests that glucocorticoids may adversely affect hepatic inflammation and fibrosis. 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 5α-reductase are implicated in the link between glucocorticoids and MASLD, the former enzyme increasing and the latter reducing the glucocorticoid action on the liver. Treatment considerations exist due to the pathogenic link between glucocorticoids and MASLD. Since iatrogenic hypercortisolism is common, glucocorticoids should be used at the minimum daily dose to control the subjective disease. Furthermore, the pharmacologic inhibition of 11β-HSD1 has provided favorable results in MASLD, both in preclinical studies and early MASH clinical trials. Summary Glucocorticoids are closely linked to MASLD pathophysiology, with specific clinical and therapeutic implications.

High dietary Fructose Drives Metabolic Dysfunction-Associated Steatotic Liver Disease via Activating ubiquitin-specific peptidase 2/11β-hydroxysteroid dehydrogenase type 1 Pathway in Mice

“…Future research endeavors should aim to decipher the complex interactions between dietary fructose, intestinal health, and the gut microbiome. Thirdly, our study discusses the well-documented correlation between 11β-HSD1 activity and cortisol conversion - a notion that is broadly acknowledged within the field 74 . Nevertheless, the validity of this association would be significantly reinforced by targeted pharmacological or genetic studies.…”

Dietary Cholest-4-en-3-one, a Cholesterol Metabolite of Gut Microbiota, Alleviates Hyperlipidemia, Hepatic Cholesterol Accumulation, and Hyperinsulinemia in Obese, Diabetic db/db Mice

“…The steroid group plays a structural role in cell membranes and contributes to physiological functions as a regulator of several important metabolic pathways as secondary messengers and hormones. For example, cortisol and synthetic cortisol-like compounds, termed as corticosteroids, help regulate blood pressure, immune function, and anti-inflammatory processes [ 2 , 3 ]. Moreover, phytosterols and phytostanols (e.g., β-sitosterol, campesterol, sitostanol, campestanol, and saringosterol) have been reported to exert biological effects, including lowering blood low-density lipoprotein cholesterol (LDL-C) levels, improving cognition function, and alleviating the pathology of Alzheimer’s disease [ 4 , 5 , 6 , 7 ].…”