See article vol. 31: 1031-1047
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and a major public health concern worldwide. Its prevalence has increased in recent years, and a meta-analysis by Younossi et al. found a global prevalence of NAFLD of 38%, which is a 1.5-fold increase since the 1990s 1) . In Japan, the prevalence is estimated to be approximately a quarter of the general population based on the results of a study of 71,254 individuals from 13 health centers 2) . NAFLD includes liver conditions, ranging from steatosis to steatohepatitis to liver cirrhosis. NAFLD is also associated with insulin resistance and components of metabolic syndrome, including obesity, type 2 diabetes, and hyperlipidemia, thereby making it a multisystem disease 3) . A meta-analysis of observational studies showed an association between NAFLD and cardiovascular disease risk 4) . These mechanisms have been suggested to involve insulin resistance and diabetes mellitus, but they are not fully understood.
In this issue of the Journal of Atherosclerosis and Thrombosis, Hirata et al. cross-sectionally analyzed the data of 928 Japanese community dwellers who participated in the Tsuruoka Metabolome Cohort Study (TMCS) to confirm the association between NAFLD and cardiac ankle vascular index (CAVI) as indicated subclinical atherosclerosis and explored the metabolites involved in both by assessing 94 metabolites through capillary electrophoresis-mass spectrometry 5) . The authors confirmed the association between NAFLD and CAVI and found that NAFLD was associated with 31 of 94 metabolites and CAVI was associated with 10 metabolites, including branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) Using a mediation analysis, they also showed that BCAAs explain more than 20% of the association between NAFLD and CAVI.
Previous studies have reported an association between NAFLD and BCAAs and AAAs 6) , and these substances have also been reported to be associated with insulin resistance. Wang et al. in the Framingham Offspring Study, which followed 2,422 people without diabetes for 12 years, found that BCAAs and higher fasting plasma levels of AAAs were associated with an increased risk of future diabetes development 7) . BCAAs have also been reported to be associated with subclinical atherosclerosis; Jiang et al. in a community-based Chinese cohort of 489 individuals, examined the association between serum levels of 38 metabolites measured by nuclear magnetic resonance and brachial-ankle pulse wave velocity and carotid intima- media thickness and found that BCAAs were associated with a risk of developing subclinical atherosclerosis 8) . Chelvi et al. examined the association between the plasma levels of 853 metabolites identified by liquid chromatography-mass spectrometry and coronary artery calcification in 700 patients with clinically diagnosed type 2 diabetes, and thus found the BCAA subpathways to be associated with coronary artery calcification 9) .
The results of the study by Hirata reconfirmed these findings, but are noteworthy in that they revealed metabolomic profiling of both NAFLD and subclinical atherosclerosis in a single study, thus providing insight into the pathogenesis of atherosclerotic disease in NAFLD. On the other hand, the participants in Hirata’s study were limited to TMCS participants with a high prevalence of cardiovascular risk factors, which may have somewhat overestimated the results. Studies in different populations are needed to verify the external validity. In addition, since this was a cross-sectional study, it was not possible to consider temporal relationships. The pathogenesis of atherosclerotic disease should therefore be examined in future prospective studies.
Conflicts of Interest
None.
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