Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr−/−.Leiden mice with manifest obesity‐associated NASH

Abstract

Non‐alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched‐chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative‐inflammatory stress. After a 26 weeks run‐in on fast food diet (FFD), obese Ldlr−/−.Leiden mice were treated for another 12 weeks with either valine or isoleucine (3% of FFD) and then compared to FFD controls. Valine and isoleucine did not affect obesity, dyslipidemia, gut permeability, or fecal fatty acid excretion, but significantly reduced hyperinsulinemia. Valine and isoleucine reduced ALT, CK18‐M30, and liver steatosis with a particularly pronounced suppression of the microvesicular component (−61% by valine and −71% by isoleucine). Both BCAAs decreased intrahepatic diacylglycerols and 4‐hydroxynonenal immunoreactivity, a marker for oxidative stress‐induced lipid peroxidation. Functional genomics analysis demonstrated that valine and isoleucine affected BCAA metabolism genes, deactivated master regulators of anabolic pathways related to steatosis (e.g., SREBPF1), and activated master regulators of mitochondrial biogenesis (e.g., PPARGC1A) and lipid catabolism (e.g., ACOX1, AMPK). This correction of critical metabolic pathways on gene expression level was accompanied by a significant decrease in histological liver inflammation, and suppression of FFD‐stimulated cytokine and chemokine proteins KC/CXCL1, MCP‐1/CCL2, and MIP‐2/CXCL2 and their pathways. In conclusion, dietary intervention with either valine or isoleucine corrected liver diacylglycerols, gene expression of multiple metabolic processes, and reduced NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins.

Molecular mechanism of valine and its metabolite in improving triglyceride synthesis of porcine intestinal epithelial cells

“…Previous studies from our laboratory indicated that optimal valine supplementation in the diet of sows could improve the weaning weight of piglets by increasing the milk fat synthesis in sows 24 , indicating that valine is closely related to fat metabolism in sow mammary glands. Recent studies in humans and rats have highlighted that the blood valine level may indicate whether lipid metabolism is balanced 25 , 26 . Although valine has been extensively studied considering the intestinal health of piglets 27 , the mechanism by which valine regulates the intestinal health of piglets is unclear.…”

The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr−/−.Leiden Mice

“…However, compared to exercising mice that did not receive BCAA supplementation, mice that both exercised and received BCAA supplementation exhibited a higher eWAT mass as a proportion of their total body weight. This result differs from the effects of isoleucine or valine monotreatment in Ldlr−/−.Leiden mice on a fructose-containing HFD [ 80 ]. In contrast, Zhang et al demonstrated that BCAA supplementation attenuated HFD-induced weight gain and decreased adipose tissue accumulation at the expense of abnormal lipolysis [ 81 ].…”

Lingguizhugan decoction improves non-alcoholic steatohepatitis partially by modulating gut microbiota and correlated metabolites

“…Besides, valine was reported to improve liver diacylglycerols, and reduce NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins (Gart et al, 2022). However, another study reported that high levels of valine could decrease gut microbiota (such as Fusobacteriota and Deferribacterota) LGZG reversed metabolites and gut microbiota, the X-axis represented metabolites, and the Y-axis represented gut microbiota, the red color showed the positive correlation, and the green color showed the negative correlation, *p < 0.05, **p < 0.01, ***p < 0.001.…”

“…Consistently, we observed that glutamic acid was lowered in NASH and restored by LGZG decoction, and its negatively correlated gut microbiota (such as Butyricimonas and Odoribacter ) was increased in NASH and decreased by LGZG. Besides, valine was reported to improve liver diacylglycerols, and reduce NASH histology with profound hepatoprotective effects on oxidative stress and inflammatory proteins ( Gart et al., 2022 ). However, another study reported that high levels of valine could decrease gut microbiota (such as Fusobacteriota and Deferribacterota) abundances and revealed the adverse metabolic response to NAFLD, which suggested reducing dietary valine as a new approach to preventing NAFLD of laying hens ( Jian et al., 2021 ).…”