Metabolite Erythritol in 24-Hour Urine Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study

The pentose phosphate pathway (PPP) furnishes NADPH for hepatic de novo lipogenesis, driving intrahepatic lipid (IHL) accumulation. The aim of the current study was to examine the association between the PPP, proxied by 24-h urinary erythritol, and IHL content at the population level. We used cross-sectional data from the Maastricht Study, a population-based cohort study (N = 1,494; mean ± SD age 59 ± 8 years; 49% women). We first assessed the relationship between 24-h urinary erythritol and IHL content (quantified with 3T Dixon MRI), with adjustment for age, sex, type 2 diabetes, proxies of socioeconomic status/lifestyle, MRI lag time, BMI, and intake of erythritol-containing food items. Second, we performed a genome-wide association study (GWAS) for 24-h urinary erythritol (N = 2,000) and Mendelian randomization (MR) study using common variants in genes associated with erythritol in relation to IHL content. In the fully adjusted model, 24-h urinary erythritol levels were associated with higher (10log) IHL content. The GWAS identified one genome-wide significant locus (rs72686491; TESK2) and replicated two previously reported genetic variants at nominal significance. MR analysis, using these three genetic instruments, did not reveal a statistically significant association between genetically predicted erythritol levels and IHL content. The findings of this population-based study show that higher PPP flux is associated with higher IHL content, a well-established risk factor for type 2 diabetes. An active role for erythritol per se was excluded by MR analysis.

The role of the pentose phosphate pathway (PPP) in the pathogenesis of intrahepatic lipid (IHL) accumulation has not been studied before in humans. Is the PPP, proxied by 24-h urinary erythritol, associated with IHL content at the population level? In the fully adjusted model, 24-h urinary erythritol levels were associated with higher IHL content. Furthermore, genetically predicted erythritol levels were not associated with liver fat, suggesting that erythritol per se is not responsible for the former observation. Findings of the current study suggest that 1) the PPP is associated with IHL content at the population level, and 2) erythritol could potentially serve as a urinary biomarker for IHL content.