Dihomo-γ-Linolenic Acid Elevation with Desaturase Imbalance in Metabolic Dysfunction-Associated Steatotic Liver Disease in a Japanese Health Checkups Cohort: HOZUGAWA Study, a Multi-Omic, Diet Adjusted Analysis.

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to dietary fat quality and polyunsaturated fatty-acid metabolism. We evaluated whether dietary n-6 fatty-acid intake, serum dihomo-γ-linolenic acid (DGLA), and desaturase-based indices for Δ5-desaturase (D5D) and Δ6-desaturase (D6D) are associated with MASLD. Methods: We conducted a cross-sectional analysis within the HOZUGAWA health checkup cohort in Japan (n = 289; 100 MASLD, 189 non-MASLD). Participants underwent hepatic ultrasonography, dietary assessment using the Brief Self-Administered Diet History Questionnaire, and fasting serum metabolomics by gas chromatography-mass spectrometry with solid-phase dehydration derivatization. Enzyme indices were defined as the D5D index = arachidonic acid/DGLA and the D6D proxy index = DGLA/linoleic acid (hereafter referred to as the D6D index) because γ-linolenic acid was not measured. Natural-log-transformed D5D index, D6D index, DGLA, and total dietary n-6 fatty-acid intake were entered into multivariable logistic regression models for MASLD adjusted for age, sex, BMI, alcohol intake, and total energy. Results: Compared with non-MASLD, MASLD showed higher serum DGLA, lower D5D index, and higher D6D index (all p ≤ 0.005), with no between-group differences in total energy intake, linoleic acid, total polyunsaturated fatty acids, or total dietary n-6 fatty-acid intake. Higher ln D5D was independently associated with lower odds of MASLD (OR 0.62, 95% CI 0.42-0.86), whereas higher ln D6D index (OR 1.42, 95% CI 1.04-1.95) and ln DGLA (OR 1.62, 95% CI 1.13-2.43) were each positively associated. Total dietary n-6 fatty-acid intake was not independently associated with MASLD. Conclusions: In this Japanese health examination cohort, an imbalance in estimated desaturase activities-lower D5D index and higher D6D index-together with higher serum DGLA was independently associated with MASLD, whereas n-6 intake showed no group difference or independent association. These findings suggest that enzyme-linked endogenous n-6 metabolic status may be more closely related to the MASLD phenotype than intake quantity alone.