Branched chain amino acids are associated with the heterogeneity of the area of lipid droplets in hepatocytes of patients with non‐alcoholic fatty liver disease

Abstract

Aim Macrovesicular steatosis around the central vein (zone 3) is one of the pathological features of non‐alcoholic fatty liver disease or steatohepatitis (NAFLD/NASH). The aim of this study is to elucidate precisely the association between the area of lipid droplets (LDs) and the plasma metabolic parameters in patients with NAFLD/NASH. Methods Eighty patients with NAFLD/NASH diagnosed by needle biopsy were enrolled. The LDs around zone 3 were counted automatically by image processing software, the total area of LDs (TLDs), the maximum area of LDs (MAXLDs), the average area of LDs (AVELDs) and the heterogeneity by the coefficient of variation (CV [%]) were quantified. The correlations between these values and plasma metabolic parameters were analyzed. We evaluated the association between branched chain amino acids (BCAAs) and the heterogeneity of LDs in hepatocytes in vitro and in vivo. Results The MAXLDs was significantly correlated with more metabolic parameters than AVELDs and TLDs. The level of BCAAs was independently associated with the CV among the metabolic parameters. In early stage NAFLD, aspartate and alanine aminotransferase were significantly higher in the high CV group than in the low CV group. The high concentration of BCAAs increased the CV of LDs in hepatocytes accompanied by the expression of phosphor‐p70 S6 kinase and sterol regulatory element‐binding protein 1 in vitro. A high BCAA diet induced high heterogeneity of LDs around zone 3 in ob/ob mice. Conclusions The levels of BCAAs were associated with the LD heterogeneity of hepatocytes around zone 3 in patients with NAFLD/NASH.

Moderate, Rather Than Vigorous Exercise Benefits Plasma Amino Acids Profile in Patients With Nonalcoholic Fatty Liver Disease

“…In particular, branched-chain amino acids (BCAAs, leucine, isoleucine, and valine) have been proved to be elevated in NAFLD patients [9], and strongly associated with increased risk of NAFLD [10], insulin resistance, obesity [11,12] and future clinical decompensation in NAFLD [13]. It was also revealed that the changes in hepatic BCAA composition were strongly associated with transcriptomic metabolism pro les during the progression of NAFLD [14]. Various exercise intensities impacted plasma metabolic pro le differently [15][16][17], for now, there were fewer studies that examined the circulating AAs alteration after exercise training [18][19][20][21][22], and the relationship between AAs metabolism and exercise intensity was little known.…”

Branched chain amino acids: A factor for zone 3 steatosis in non‐alcoholic fatty liver disease

“…Besides the known mechanisms for zone 3 steatosis, a recent study by Kakazu et al . was the first to show that BCAAs are an independent factor associated with the steatosis in zone 3 hepatocytes in patients with NAFLD/NASH . Although higher serum level of BCAAs have been reported in a mouse model of NASH as well as in patients with NAFLD/NASH, Kakazu et al .…”

“…The recent article by Kakazu et al . showed that branched‐chain amino acids (BCAAs) are associated with the heterogeneity of hepatic steatosis in patients with NAFLD/NASH . Their findings indicated that an alteration in BCAA metabolism might be a pathological condition of NAFLD/NASH.…”

“…Although higher serum level of BCAAs have been reported in a mouse model of NASH as well as in patients with NAFLD/NASH, Kakazu et al . precisely quantified the steatosis area using an imaging technique and showed the heterogeneity of hepatic steatosis . Circulating BCAAs are known to be negatively correlated with insulin sensitivity in patients with NAFLD .…”

“…Kakazu et al . also showed that treatment with oleic acid and BCAAs upregulated the expression of sterol regulatory element binding protein 1 and phospho‐p70S6K in hepatocytes in vitro , and caused heterogeneity of hepatic steatosis in ob / ob mice . Based on their results, the authors were doubtful about the efficacy of BCAA supplementation for the early stage of NAFLD with high BCAA levels.…”