Obeticholic acid's effect on HDL function in MASH varies by diabetic status

Area of Science:

• Hepatology
• Cardiology
• Endocrinology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) and atherosclerosis share inflammatory and oxidative stress pathways.
• Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise for MASH but may increase cardiovascular disease (CVD) risk by reducing HDL cholesterol.

Purpose of the Study:

• To investigate the effects of OCA on HDL cholesterol efflux, antioxidant capacity, and pro-inflammatory index in patients with MASH, comparing diabetic and nondiabetic individuals.
• To assess potential differences in OCA's impact on cardiovascular risk markers between diabetic and nondiabetic MASH patients.

Main Methods:

• Assessed HDL cholesterol efflux function, antioxidant (paraoxonase, ceruloplasmin activity), pro-inflammatory index, and particle sizes in MASH patients (10 diabetic, 10 nondiabetic) before and after 18 months of OCA treatment.
• Excluded patients on lipid-lowering medications.
• Analyzed baseline ferritin levels and changes in HDL function markers and liver enzymes post-treatment.

Main Results:

• OCA improved liver histology and enzymes but increased alkaline phosphatase in nondiabetics.
• OCA did not significantly alter cholesterol efflux or paraoxonase function.
• In nondiabetics, OCA decreased ceruloplasmin activity and increased HDL's pro-inflammatory index.
• In diabetics, OCA increased protective pre-β-HDL levels without altering overall HDL functionality.
• Serum glucose levels negatively correlated with OCA-induced changes in HDL pro-inflammatory function, primarily due to diabetes.

Conclusions:

• OCA exhibits distinct effects on HDL functionality in diabetic versus nondiabetic MASH patients.
• The differential impact on HDL may influence CVD risk, particularly in nondiabetic MASH patients.
• Further large-scale studies are warranted to confirm these preliminary findings and elucidate clinical implications.