Improving Screening and Identifying Therapeutic Targets for NAFLD

The Challenge: Improving Screening and Identifying Therapeutic Targets for NAFLD

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of people who drink little or no alcohol. It is currently recognized as one of the world’s most common etiologies of chronic liver disease. NAFLD is a form of hepatic steatosis that can progress to hepatic fibrosis. Given the epidemic increase of NAFLD cases and its association with high morbidity and mortality, there is a need to better characterize the heritability of NAFLD to understand its pathogenesis, identify potential therapeutic targets, and improve the screening of the patients who are at a higher risk of progression to hepatic fibrosis. Metabolomics can provide new insights into the molecular mechanisms of diseases, including NAFLD.

Metabolon Insight: Uncovering Shared Gene-Effect with Hepatic Steatosis and Fibrosis

This study utilized the Metabolon Global Discovery Panel to profile sera from a twin and family cohort with (n = 36) and without (n = 120) NAFLD.¹ Among the NAFLD individuals, 36 had hepatic steatosis and 28 had progressed to liver fibrosis. The Global Discovery Panel’s unrivaled coverage of up to 5,400 metabolites offered this group the most comprehensive solution to investigate whether NAFLD is heritable, whether there is a shared gene-effect with hepatic steatosis and fibrosis, and if gut-derived metabolites mediate this shared gene-effect.

The Solution: Metabolomics Identifies a Gut Microbiome Derived Metabolite Associated with NAFLD

Metabolomics detected 1,181 metabolites in the serum of the twin and family cohort. Among the 713 metabolites analyzed, 153 belonging to eight super pathways (eg, amino-acid, lipid, and carbohydrate) were significantly differentially expressed in individuals with NAFLD compared to individuals without NAFLD, and 86 belonging to eight super pathways were significantly differentially expressed in individuals with liver fibrosis compared to individuals without fibrosis.

This research group then used a twin additive genetics and unique environment effects model to estimate the shared gene-effect. Among the 713 serum metabolites analyzed in the twins, 440 serum metabolites were heritable. Among the 440 heritable serum metabolites identified, 170 serum metabolites had a significant shared gene-effect with hepatic steatosis and 94 serum metabolites had a significant shared gene-effect with hepatic fibrosis. Among them, 56 serum metabolites had a significant shared gene-effect with hepatic steatosis and fibrosis. Interestingly, among these 56 serum metabolites, six metabolites had a microbial origin and derived potentially from the gut microbiome: 3-(4-hydroxyphenyl)lactate, N-formylmethionine, phenyllactate, mannitol, allantoine, N-(2-furoyl)glycine. Finally, these findings were validated in an independent validation cohort of 156 participants with liver biopsy-proven NAFLD. Among all metabolites, only 3-(4-hydroxyphenyl)lactate was significantly associated with hepatic fibrosis in this cohort.

The Outcome: Elucidating a Novel Biomarker of NAFLD

Utilizing the twin and family cohort and a validation cohort of patients with biopsy-proven NAFLD, this study reports the association between a gut microbiome-derived serum metabolite, 3-(4-hydroxyphenyl)lactate that has a statistically and clinically significant shared gene-effect with both hepatic steatosis and fibrosis. These results suggest a common genetic basis underlying the susceptibility towards NAFLD-related fibrosis and 3-(4-hydroxyphenyl)lactate pathway and their joint association with the gut microbiome. Targeting specific nodal points in this metabolic pathway could have a major therapeutic impact on NAFLD. In addition, 3-(4-hydroxyphenyl)lactate could be a useful biomarker for the screening of patients at risk of an advanced stage of NAFLD or could be used for monitoring the targeted therapeutic response when modulating the microbiome to affect hepatic fibrosis in NAFLD.