PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids.

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.

Clinical Intervention to Reduce Dietary Sugar Does Not Affect Liver Fat in Latino Youth, Regardless of PNPLA3 Genotype: A Randomized Controlled Trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) among Latinos is partially attributed to a prevalent C>G polymorphism in the patatin-like phospholipase 3 (PNPLA3) gene. Cross-sectional analyses in Latino children showed the association between dietary sugar and liver fat was exacerbated by GG genotype. Pediatric feeding studies show extreme sugar restriction improves liver fat, but no prior trial has examined the impact of a clinical intervention or whether effects differ by PNPLA3 genotype. OBJECTIVES: We aimed to test effects of a clinical intervention to reduce dietary sugar compared with standard dietary advice on change in liver fat, and secondary-endpoint changes in liver fibrosis, liver enzymes, and anthropometrics; and whether effects differ by PNPLA3 genotype (assessed retrospectively) in Latino youth with obesity (BMI ≥ 95th percentile). METHODS: This parallel-design trial randomly assigned participants (n = 105; mean baseline liver fat: 12.7%; mean age: 14.8 y) to control or sugar reduction (goal of ≤10% of calories from free sugar) for 12 wk. Intervention participants met with a dietitian monthly and received delivery of bottled water. Changes in liver fat, by MRI, were assessed by intervention group via general linear models. RESULTS: Mean free sugar intake decreased in intervention compared with control [11.5% to 7.3% compared with 13.9% to 10.7% (% energy), respectively; P = 0.02], but there were no significant effects on liver outcomes or anthropometrics (Pall > 0.10), and no PNPLA3 interactions (Pall > 0.10). In exploratory analyses, participants with whole-body fat mass (FM) reduction (mean ± SD: -1.9 ± 2.4 kg), irrespective of randomization, had significant reductions in liver fat compared with participants without FM reduction (median: -2.1%; IQR: -6.5% to -0.8% compared with 0.3%; IQR: -1.0% to 1.1%; P < 0.001). CONCLUSIONS: In Latino youth with obesity, a dietitian-led sugar reduction intervention did not improve liver outcomes compared with control, regardless of PNPLA3 genotype. Results suggest FM reduction is important for liver fat reduction, confirming clinical recommendations of weight loss and a healthy diet for pediatric NAFLD.This trial was registered at clinicaltrials.gov as NCT02948647.