Higher plasma dicarbonyl levels are associated with liver fibrosis in obese individuals.

Introduction: Methylglyoxal (MGO) is a very reactive compound that modifies proteins, forming advanced glycation end products (AGEs) and activating inflammatory pathways. Elevated MGO levels have been linked to various diseases, including type 2 diabetes and atherosclerosis. However, the role of MGO and other glycating agents in the progression of liver fibrosis in the setting of metabolic dysfunction associated steatotic liver disease (MASLD) is poorly understood.

Methods: This study explores the relationship between plasma MGO levels and related dicarbonyls (glyoxal (GO) and 3-deoxyglucosone (3-DG)), which are measured using ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and liver fibrosis assessed via histological liver biopsy scoring and the Fibrosis-4 (FIB-4) Index. The study population comprised 264 severely obese individuals due to undergo bariatric surgery, a subset from the BARIA cohort (22% type 2 diabetes; 77% females; median age 47 (IQR: 39-54 years); BMI 39 (IQR: 36-41 kg/m)).

Results: MGO levels were significantly higher in individuals with type 2 diabetes compared with individuals without type 2 diabetes, with a median of 288 nmol/L (257-334 nmol/L) and 238 (212-279 nmol/L) respectively. MGO levels were higher in males compared with females, with a median of 267 (236-301 nmol/L) and 245 (214-288 nmol/L) respectively. Similar results were found for GO and 3DG. Higher plasma MGO, GO and 3DG levels were significantly associated with the FIB-4 Index (MGO, rho = 0.21, p < 0.01), (GO, rho = 0.29, p < 0.01), (3DG, rho = 0.25, p < 0.05). Using linear regression models, the association between MGO and the FIB-4 Index remained significant after adjustment for age (years), sex, BMI, sub-cohort, smoking status, alcohol consumption, hypertension, HOMA-IR, HbA1c and fasting glucose levels. Using ordinal logistic regression models, MGO and GO were also associated with liver fibrosis scoring from biopsy before and after adjustment for confounders (Age (years), sex, BMI, sub-cohort, smoking status, alcohol consumption, hypertension, HOMA-IR, HbA1c and fasting glucose levels). Notably, the relationships remained significant in individuals without type 2 diabetes and after adjusting for HbA1c and fasting glucose levels. No significant associations were observed between MGO, GO, or 3DG and steatosis or inflammation histology scores after adjustment for confounders.

Conclusion: This study shows the potential role of dicarbonyl stress, particularly MGO, in liver fibrosis among obese individuals, highlighting its significance as an independent contributor to liver damage and a potential therapeutic target.