Relation between cortisol and metabolic dysfunction-associated steatotic liver disease: A dog chasing its tail

Table 3 Summary of the main enzymes involved in hepatic cortisol metabolism and their role in metabolic dysfunction-associated steatotic liver disease. The table highlights enzyme function, expression changes across disease stages, effects on hepatic steatosis, and potential therapeutic implications

Enzyme	Primary function	Hepatic expression	Effects on hepatic steatosis	Possible therapeutic implications
11β-HSD1	Converts inactive cortisone to active cortisol; amplifies intracellular cortisol action	Reduced in early steatosis; increased in MASH	Overexpression promotes lipogenesis and fat accumulation; knockout protects against steatosis	Inhibition may provide reduction in liver steatosis
11β-HSD2	Inactivates cortisol to cortisone	Not extensively studied in MASLD	Primarily renal/placental function; limited hepatic role in MASLD	Not a primary therapeutic target at the moment for MASLD
5α-reductase type 1	Converts cortisol to 5α-dihydrocortisol (retains some GR activity); converts testosterone to DHT	Increased in steatosis	Deficiency/inhibition increases steatosis but protects against HCC; mediates metabolic effects	Dual inhibitors (dutasteride) increase hepatic lipid accumulation. Selective type 2 inhibitors (finasteride) have no effect on steatosis
5α-reductase type 2	Converts cortisol to 5α-dihydrocortisol; converts testosterone to DHT in reproductive tissues	Primarily reproductive tract expression	Minimal metabolic effects; deficiency does not increase steatosis	Limited metabolic relevance
5β-reductase (AKR1D1)	Converts cortisol to 5β-dihydrocortisol (biologically inactive); major cortisol inactivation pathway	Variable in early disease; reduced with progressive fibrosis	Knockdown promotes lipid accumulation via increased de novo lipogenesis	Increasing its activity may have a potential protective role

MASLD: Metabolic dysfunction-associated steatotic liver disease; 11β-HSD1: 11β-hydroxysteroid dehydrogenase type 1; MASH: Metabolic dysfunction associated steatohepatitis; 11β-HSD2: 11β-hydroxysteroid dehydrogenase type 2; GR: Glucocorticoid receptor; DHT: Dihydrotestosterone; HCC: Hepatocellular carcinoma.