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. Glucocorticoids are closely linked to MASLD pathophysiology, with specific clinical and therapeutic implications.

Keywords: Adrenals; Cortisol; Glucocorticoids; Metabolic dysfunction-associated steatohepatitis; Metabolic dysfunction-associated steatotic liver disease; Nonalcoholic fatty liver disease.

Fig. 1

Pathophysiology of GC-induced MASLD. Endogenous and exogenous GC enter the hepatocytes, where they bind their specific GR and move into the nucleus, affecting the transcription of multiple genes. At the same time, GC may also repress the expression of the Hes1 gene, which is regarded as a prerequisite for their action. GC action is enhanced by the activity of 11β-HSD1, which converts the inactive cortisone to active cortisol both in the hepatocytes and adipocytes. The primary actions of GC in the hepatocyte are: decrease in IRS-1 and PI3K phosphorylation, i.e., attenuating the action of key intracellular molecules of insulin signaling, thus inducing IR; IR is further impaired by the GC-induced decrease in glucose uptake in the skeletal muscle; increase in gene transcription of key intracellular molecules of hepatic gluconeogenesis, e.g., the G6Pase, which contributes to the final steps of gluconeogenesis; GC-induced protein degradation, e.g., in the skeletal muscle, provides amino acids as substrates for hepatic gluconeogenesis; decrease in fatty acid β-oxidation and in VLDL export from the hepatocytes, whereas simultaneously more FFAs enter the hepatocytes, owing to the GC-induced lipolysis in the adipose tissue; consequently, TG are accumulated into the hepatocytes and hepatic lipotoxicosis may occur; and increase in hepatic de novo lipogenesis, using carbohydrates as substrates, e.g., fructose or glucose, thus further increasing hepatic TG accumulation. Abbreviations: 11β-HSD1, 11beta-hydroxysteroid dehydrogenase type 1; AA, amino acid; FFA, free fatty acid; G6Pase, glucose-6-phosphatase catalytic subunit; GC, glucocorticoids; GR, glucocorticoid receptor; Hes1, hairy enhancer of the split 1; IR, insulin resistance; IRS, insulin receptor substrate; MASLD, metabolic dysfunction-associated steatotic liver disease; P, phosphoryl group; PI3K, phosphatidylinositol-3-kinase; TG, triglyceride; VLDL, very low-density lipoprotein