Changed Amino Acids in NAFLD and Liver Fibrosis: A Large Cross-Sectional Study without Influence of Insulin Resistance

Abstract

Altered amino acid levels have been found in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, it is not clear whether this alteration is due to altered hepatic metabolism or insulin resistance. The aim of this study was to clarify the association among amino acid levels, fatty liver, and liver fibrosis while eliminating the influence of insulin resistance. NAFLD and liver fibrosis were diagnosed using transient elastography and subjects were divided into three groups: normal, NAFLD, and liver fibrosis. To exclude the influence of insulin resistance, the subjects were matched using the homeostasis model assessment of insulin resistance (HOMA-IR). The amino acid serum levels were compared among the groups. Of 731 enrolled subjects, 251 and 33 were diagnosed with NAFLD and liver fibrosis. Although significant differences were observed among the groups in the serum levels of most amino acids, all but those of glutamate and glycine disappeared after matching for HOMA-IR. The multivariate logistic regression revealed that glutamate, glycine, and HOMA-IR were independent risk factors for liver fibrosis. The altered serum levels of most amino acids were associated with insulin resistance, while the increase in glutamate and the decrease in glycine levels were strongly associated not only with insulin resistance, but also with altered liver metabolism in patients with liver fibrosis.

Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes

“…As discussed before, most of the dysregulated amino acids in this study are associated with insulin resistance suggesting that participants with T2D in this study are at high risk of developing NAFLD. In addition, a previous study revealed that high Glu levels had a significant pathological role in the development of liver fibrosis independently from insulin resistance (Hasegawa et al, 2020). In this study, Glu level was significantly higher in T2D and together with increased TG and LDL could increase the risk of future liver fibrosis as well as cardiovascular complications.…”

Plasma Amino Acids and Residual Hypertriglyceridemia in Diabetic Patients Under Statins: Two Independent Cross-Sectional Hospital-Based Cohorts

“…Apart from BCAA, we also identify a positive association between Ala and TG as several previous studies in non-diabetes (30,39). Ala plays a key role in the glucose-alanine cycle between tissues and the liver.…”

“…Besides, the associations were robust in the context of LDL-C, suggesting that abnormal amino Although the relationships between amino acids and lipid abnormality were yet completely clarified, their associations have been investigated in many studies. Compared with healthy controls, patients with abnormal BMI or non-alcoholic fatty liver disease have profound perturbation of amino acid metabolism (29,30). Several cross-sectional and longitudinal studies also showed that amino acid signature significantly predicted future hypertriglyceridemia in children (31,32).…”

Correlation guided Network Integration (CoNI) reveals novel genes affecting hepatic metabolism

“…In contrast, the metabolite sub-networks of the HFD-derived LCGs Smim13 and Rapgef4 not only included BA, PC, LPC, and AC metabolites, but also their subgraphs were interconnected by an overlapping mixture of AA. An impaired AA metabolism was previously linked to NAFLD and liver fibrosis [ 26 , 27 ]. The third HFD sub-network was under the control of the LCG Inhbe and contained only AC which is known to be involved in fat metabolism, especially in the carnitine shuttle transporting long-chain fatty acids into mitochondria [ 28 ].…”