Background: Patatin-like phosphatase domain-containing 3 ( PNPLA3 ) gene and dietary fat are important factors for metabolic dysfunction-associated steatotic liver disease (MASLD). Objective: We studied the impact of dietary fat quality modification on liver adiposity in men homozygotes for PNPLA3 (GG, carriers of the risk allele and CC, non-carriers). Methods: Ninety-eight men (age: 67.8 ± 4.2 years, body mass index: 27.2 ± 2.5 kg/m ² ), homozygous for PNPLA3 rs738409 variant (I148M), randomly assigned for two diet intervention arms, participated in a 12-week diet intervention. Recommended diet (RD) arm ate fat according to the National and Nordic nutrition recommendations, average diet (AD) arm ate according to the average fat intake in Finland. Liver imaging by ultrasound with 2D-shear wave elastography (2D-SWE) and magnetic resonance imaging (MRI) in combination with magnetic resonance spectroscopy (MRS) were performed. Results: MRI-based liver fat proportion decreased in the RD arm (CC: from 3.8 ± 3.2 to 3.2 ± 3.3%, GG: from 3.9 ± 3.3 to 3.5 ± 3.1%, p time = 0.032) and increased in the AD arm (CC: from 4.1 ± 3.6 to 4.8 ± 3.9%, GG: from 4.7 ± 3.7 to 6.7 ± 5.3%, p time = 0.015). MRS-quantified liver saturated fat content increased in the AD arm in both genotypes of PNPLA3 ( p time = 0.010). Liver triglyceride concentration did not change in either arm with the CC genotype but increased in the AD arm with the GG genotype (for time and genotype interaction p = 0.027). Conclusion: Diet based on fat quality recommendations could be beneficial for liver health in both PNPLA3 genotypes CC and GG. The average diet seems to be especially harmful for liver health in carriers of the PNPLA3 risk genotype (GG).

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m²) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.