Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a globally widespread disease of increasing clinical significance. The pathological progression of the disease from simple steatosis to nonalcoholic steatohepatitis (NASH) has been well defined, however, the contribution of altered branched chain amino acid metabolomic profiles to the progression of NAFLD is not known. The three BCAAs: leucine, isoleucine and valine are known to mediate activation of several important hepatic metabolic signaling pathways ranging from insulin signaling to glucose regulation. The purpose of this study is to profile changes in hepatic BCAA metabolite levels with transcriptomic changes in the progression of human NAFLD to discover novel mechanisms of disease progression. Metabolomic and transcriptomic data sets representing the spectrum of human NAFLD (normal, steatosis, NASH fatty, and NASH not fatty livers) were utilized for this study. During the transition from steatosis to NASH, increases in the levels of leucine (127 % of normal), isoleucine (139 %), and valine (147 %) were observed. Carnitine metabolites also exhibited significantly elevated profiles in NASH fatty and NASH not fatty samples and included propionyl, hexanoyl, lauryl, acetyl and butyryl carnitine. Amino acid and BCAA metabolism gene sets were significantly enriched among downregulated genes during NASH. These cumulative alterations in BCAA metabolite and amino acid metabolism gene profiles represent adaptive physiological responses to disease-induced hepatic stress in NASH patients.

Amino Acid Metabolism is Altered in Adolescents with Nonalcoholic Fatty Liver Disease—An Untargeted, High Resolution Metabolomics Study

“…In addition, we observed that plasma tyrosine levels were positively associated with the severity of steatosis in the liver, even after adjusting for age, sex, BMI z-score, and HOMA-IR. This finding is supported by a previous study analyzing frozen liver samples, which showed increased hepatic tyrosine levels in steatohepatitis when compared with simple steatosis alone (25). We expanded this observation to the pediatric population and furthered it by demonstrating an independent correlation between tyrosine levels and hepatic steatosis regardless of obesity and insulin resistance.…”

“…Because liver is a critical organ for amino acid homeostasis, the imbalances could be a consequence of abnormal liver function. BCAA (leucine, isoleucine, valine) have been the most frequently investigated and observations from case control studies indicate higher BCAA levels in adults with NAFLD when compared with age- and sex-matched controls (25, 32); however, it remains unknown whether this elevation is confounded by insulin resistance. Even though elevated plasma BCAA and its dysregulated metabolism are evident during insulin resistance and type 2 diabetes (21, 24), the role of BCAA in the pathogenesis of NAFLD, particularly in children, remains unsolved.…”

Metabonomics studies on serum and urine of patients with breast cancer using 1H-NMR spectroscopy

“…Serum amino acid levels between esophageal cancer, osteosarcoma, lymphoma and soft tissue sarcoma showed inconsistencies. Experiments in vitro showed that the consumption of arginine, threonine, taurine and glutamine in liver cancer cells increased significantly [23]. Ye et al [24] confirmed that serum concentration of tyrosine, glycine, glutamine, alanine, valine and isoleucine in cervical cancer patients was significantly lower than those in healthy controls.…”

Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy

“…However, recent studies demonstrate elevated circulating BCAA are strongly associated with NAFLD-related metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (Lynch and Adams, 2014). Moreover, as opposed to patients with simple fatty liver, hepatic BCAA accumulation is a signature metabolic finding in patients with steatohepatitis (Lake et al, 2015). Finally, downregulated expression of hepatic BCAA-degrading enzymes is also a hallmark of non-alcoholic fatty liver (Lake et al, 2015, Mardinoglu et al, 2014).…”

“…Moreover, as opposed to patients with simple fatty liver, hepatic BCAA accumulation is a signature metabolic finding in patients with steatohepatitis (Lake et al, 2015). Finally, downregulated expression of hepatic BCAA-degrading enzymes is also a hallmark of non-alcoholic fatty liver (Lake et al, 2015, Mardinoglu et al, 2014). Together, these clinical studies strongly suggest BCAA intake may have negative impact upon liver structure/function, particularly in obesity.…”