Research highlight: Examining the metabolic effects of non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases globally, characterized by an accumulation of excess lipids in the liver (hepatic steatosis). The prevalence of NAFLD continues to increase, alongside obesity, in many developed countries. For example, in the United States NAFLD has risen from 18% in 1988-1991 to 31% in 2011-2012.1 

Fatty liver has been proposed to result in dyslipidemia due to increased secretion of very low-density lipoproteins (VLDL) and impaired clearance of intermediate and low-density lipoproteins (IDL, LDL) from circulation. Detailed metabolic profiling of NAFLD patients supports this theory, with previous studies finding that fatty liver associates with multiple metabolic aberrations. Triglycerides in VLDL particle subfractions and VLDL particle concentration have shown the most prominent association with fatty liver. In addition, robust associations have been reported with several non-lipid measurements, such as amino acids leucine and isoleucine. Despite these findings, there is currently no clear consensus on the characteristic metabolic effects of NAFLD on circulating metabolites. 

In order to elucidate the molecular mechanisms behind fatty liver related metabolic aberrations, Sliz and colleagues compared metabolic associations of NAFLD with the association profiles of NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 loci. Nightingale’s NMR-based blood biomarker assay was used to identify the metabolic association profile of NAFLD by quantifying 123 metabolic measures in 1,810 individuals (N fatty liver =338) from The Cardiovascular Risk in Young Finns Study. Metabolic risk association profiles of NAFLD risk alleles were obtained from a metabolomics genome-wide association study (GWAS) of 24,925 Europeans. 

A total 85 metabolites were found to associate with NAFLD. NAFLD cases had significantly higher concentrations of total triglycerides and triglyceride levels in all lipoprotein subclasses (with the exception of very large high-density lipoproteins), along with elevated levels of glucose, lactate, pyruvate, glycerol and several amino acids (alanine, isoleucine, leucine, valine, phenylalanine and tyrosine). Among the genetic associations of NAFLD risk alleles, GCKR rs1260326-T showed high concordance with the NAFLD metabolic association profile, especially in terms of circulating lipids and lipoproteins. In contrast, no significant associations were observed for the strongest genetic risk factor (PNPLA3 rs738409-G). Further, TM6SF2 rs58542926-T showed cardioprotective metabolic effect. To summarize, these robust NAFLD risk increasing alleles showed clearly distinct association profiles on metabolic measures. 

The heterogeneous metabolic effects of the NAFLD risk alleles highlight distinct molecular pathways leading to fatty liver. These pathways include hepatic lipid accumulation (GCKR rs1260326-T), reduced VLDL secretion (TM6SF2 rs58542926-T) and impairment of triglyceride mobilization from hepatic lipid storage (PNPLA3 rs738409-G). Notably, hepatic lipid accumulation may have neutral metabolic effects. This study illustrates how combining genetic and metabolic profiling could enhance better classification and targeted treatment of NAFLD subtypes. 2  

Further reading

Access the full paper here and learn more about how Nightingale’s technology has been used to investigate genetic metabolite associations here. Nightingale's blood anlysis service has been successfully used in a wide range of research applications and has featured in over 100 peer-reviewed studies. 

References

1. Le et al. Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367688/

2. Sliz et al. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR, and LYPLAL1 show divergent metabolic effects. Human Molecular Genetics. 2018. https://doi.org/10.1093/hmg/ddy124