Role of Branched-Chain Amino Acids in Liver Diseases

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Qiao Zhan	--	2149	2022-06-30 03:38:41	\|
2	format correction	Dean Liu	-1 word(s)	2148	2022-06-30 04:18:22	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10061444

Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC).

branched-chain amino acids liver diseases non-alcoholic fatty liver disease

1. Circulatory BCAAs Level as an Indicator of a Dysmetabolic State

1.1. High Circulatory BCAAs Level in NAFLD Patients

In contrast to the documented beneficial effect of BCAA supplementation in cell culture models, higher BCAA circulatory levels were found in NAFLD patients ^[1]^[2]^[3]. The rise in BCAA levels has also been positively associated with insulin resistance (IR) and total cholesterol and glycerol levels in type 2 diabetes (T2D) and obese patients ^[4]^[5]. Since T2D and obesity are known to be risk factors for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) ^[6], this raised the question of whether the BCAA level is influenced by these underlying risk factors.

A large-scale clinical study on NAFLD subjects without T2D provided insight into the synergistic effect of NAFLD and the elevated BCAA levels on the development of type 2 diabetes. The total plasma BCAAs were positively correlated with a high fatty liver index (FLI), which was calculated from the levels of blood triglycerides, blood gamma-glutamyl-transferase, BMI, and waist circumference. In the 7.3-year follow-up analysis, nearly 20% of patients with elevated FLI were found to develop T2D. This elevation was suggested to be linked with the impaired hepatic mitochondrial function and increased mitochondrial lipid β-oxidation in NAFLD ^[1]. Although there is no causative relationship between T2D and the high BCAA circulatory levels in NAFLD, BCAA levels were positively correlated with T2D incidence ^[7]. The activity and expression of BCAA catabolic enzymes were previously reported to be altered in pathologic conditions involving metabolic disorders, in which they are downregulated in patients with type 2 diabetes ^[8].

Patients with both NAFLD and obesity have a higher BCAA circulatory level than non-obese NAFLD patients. In an Italian cohort with non-obese NAFLD patients, obese NAFLD patients, and healthy subjects, the rise in BCAA levels was more profound in the obese NAFLD group when compared to the healthy control, while valine and isoleucine levels were only significantly higher in the obese NAFLD group ^[9]. These findings aligned with observations from a study on NAFLD patients with severe obesity, where plasma BCAAs were positively correlated with steatosis stages and liver fat content ^[10]. A study illustrated the metabolic differences between obese subjects with and without progression to NAFLD. BCAAs were found to be increased in NAFLD-obese patients, but not in obese or lean healthy subjects. Further univariate analysis identified isoleucine as one of the factors that discriminates between obese patients vs. obese NAFLD patients. The study highlighted the crucial association between impaired BCAA metabolism and the manifestation of NAFLD ^[11]. In obese NAFLD patients, a higher consumption of BCAAs was associated with worse hepatic health in terms of liver fat content ^[12].

The elevated BCAAs levels were also found to contribute to IR. IR was also found to be positively correlated with the rise in BCAA levels in NAFLD and fibrosis patients ^[1]^[13]. The circulatory levels of BCAAs were positively correlated with the insulin-resistance index, HOMA-IR ^[13]. It was suggested that BCAAs may lead to IR through activating the mTORC1 signaling pathway, which produces the chronic phosphorylation of mTOR and IRS1_Ser307 ^[14]. However, recent findings found that an increase in mTORC1 signaling from BCAA consumption alone would not affect insulin sensitivity in the long term ^[15].

The rise in plasma BCAA levels in NAFLD patients was also found to be sex-dependent. Male subjects were found to have significantly higher BCAA levels than female subjects. Plasma BCAA levels in female subjects were correlated with NAFLD and fibrosis stages, while the opposite result was found in male subjects. Leucine and valine were inversely correlated with NAFLD stages in males. Nevertheless, without considering the gender differences, leucine and isoleucine were significantly associated with NAFLD stages ^[16].

Since circulatory BCAA levels were consistently found to be significantly increased in liver diseases, the possibility of using circulating BCAAs’ concentration as a diagnostic tool was suggested. A study on obese children found a high area under the curve (AUC), 0.92 (95% confidence interval 0.83–1.00), for using BCAA to discriminate between severe steatosis and a healthy obese subject, while an AUC of 0.82 (95% CI 0.67–0.97) could be used for the discrimination of any steatosis ^[10]. The elevation in BCAAs was not limited to their systematic levels. BCAA level was elevated in liver tissue in NASH patients vs. healthy subjects. However, the liver BCAA levels were found to be unchanged in simple steatosis/NAFLD patients vs. healthy subjects ^[17]. Although the study only included data from a limited number of patients, it suggested that the change in systematic levels is aligned with the local level in NASH patients, which might contribute to the activation of the aforementioned mTOR pathway ^[18].

1.2. Rising BCAA Levels in HCC Patients

Plasma BCAA levels were found to be significantly increased and have been identified as a biomarker of progression to HCC ^[19]. A low BCAAs/tyrosine ratio (≤4.4) was found to be a prognostic factor for HCC patients with chronic liver diseases. The BCAAs/tyrosine ratio was significantly negatively correlated with the liver function marker, albumin albumin-bilirubin (ALBI) ^[20]^[21].

The rise in BCAAs was not limited to their systemic level. A recent study found an increase in tissue BCAA level in HCC patients with severe fibrosis and cirrhosis. In 52 paired HCC tumor and nontumor tissues, BCAAs were found to be elevated in HCC tissue when compared with adjacent non-tumoral tissues ^[22]. The same finding was also found in another study with paired HCC tumor and nontumor tissues from 48 of their patients ^[23]. The team took a further look into the transcriptomic profile of HCC tumors and adjacent tissues of patients in both Singapore General Hospital and data from the Cancer Genome Atlas ^[23]. They found that the BCAA degradation pathway was a significantly enriched KEGG pathway in the tumors of both their 48 HCC patients and the HCC cohort from the Cancer Genome Atlas. More than 40 BCAA catabolic enzymes, including BCKDH and acyl-CoA dehydrogenase enzymes (ACADs), were suppressed in tumors. The accumulation of BCAA in the tumor activated mTORC1 signaling. A higher expression of the catabolic enzyme of BCAA was, therefore, linked to better survivability for patients. The group further investigated the impact of BCAAs on tumor development by using diethylnitrosamine (DEN)-injected high-fat diet-fed mice. Tumor number and size were elevated in the BCAA-fed group. Consistent with their findings in human subjects, BCAA catabolic enzymes were suppressed in BCAAs/DEN-injected mice, while they were enhanced in control mice fed with BCAAs.

In livers of HCC patients, and animal models, including high-fat diet-induced obesity and HCC tumor models, BCKDH activity and expression were found to be downregulated, and BCKDH kinase (BCKDK), the enzyme responsible for suppressing the activity of BCKDH, was found to be upregulated ^[24]. The consequence of this is an inability to fully oxidize BCKAs. The accumulation of BCKAs, especially from valine and isoleucine metabolism, may lead to mitochondrial dysfunction. It was previously reported that increased BCKA levels suppress the expression of succinate dehydrogenase, which affects the TCA cycle and the electron transport chain ^[25]. As a result, acylcarnitine byproducts were formed instead of the complete TCA cycle, and this elevation of plasma acylcarnitine is considered a marker of IR, type 2 diabetes, and cardiovascular diseases ^[24]. Meanwhile, in an animal and human HCC tumor model, the dysregulation of BCAA oxidation was found to induce chronic mTORC1 activation ^[23].

2. BCAA as a Treatment for Liver Diseases

2.1. BCAA as a Therapeutic Treatment in Humans

Despite the association between elevated blood BCAA levels and negative conditions in liver diseases, the consumption of BCAA supplements was previously linked to a beneficial outcome in various liver diseases, especially during advanced fibrosis or cirrhosis, and especially hepatic encephalopathy. BCAA supplementation is recommended to cirrhotic patients according to the guidelines of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) ^[26].

In three separate studies, the supplementation of BCAAs in the diet of patients with advanced liver cirrhosis resulted in a significant improvement in major cirrhosis-related events, including improvements in Child–Pugh (CP) score, MELD score, and/or a significantly higher number of patients with event-free survival ^[27]^[28]^[29]. The beneficial effect of BCAA supplementation was not limited to cirrhotic patients. BCAA supplementation was also found to be useful in preventing the occurrence of HCC in cirrhotic patients ^[30]. The majority of HCC patients (80–90%) were diagnosed with underlying cirrhotic conditions ^[31]. Although there have been few human trials on BCAA supplementation in HCC patients, increasing evidence from animal studies provides an indication of the potential beneficial effect of BCAAs.

2.2. BCAA as a Prophylactic Treatment of Liver Diseases in Animals

A DEN-injected rat liver injury model showed that BCAAs significantly lowered dysplastic nodules. Although BCAAs could not prevent progression to malignant tumors, the supplementation prevented liver neoplasm lesions ^[32]. This effect was due to the suppression of tumor angiogenesis as a result of the low secretion of VEGF. BCAA(s) was also previously found to boost the efficacy of the chemotherapy drug, cisplatin, which is widely used for the treatment of cancers. The supplementation of leucine increased cisplatin sensitivity by activating the mTOR pathway ^[33].

Over the course of NAFLD/NASH progression, cirrhosis may also develop; therefore, BCAA supplementation has also been increasingly investigated to treat these diseases, and/or prevent them from progressing to cirrhosis. Although there is a lack of human studies utilizing BCAAs to treat NAFLD or NASH patients, some animal studies have pointed to a potential positive outcome of its utilization, although the results are controversial and not conclusive. In a choline-deficient, high-fat diet-induced NASH mice model, BCAA lowered serum ALT levels and hepatic triglyceride, while the liver histology showed that the lipid droplet area and fatty acid synthase (FAS) were lowered ^[34]. Similar results were obtained from high-fat (45%) diet NAFLD rat and obese mice models, where BCAA supplementation decreased fat accumulation and triglyceride concentration in the liver, and significantly lowered the steatosis score ^[35]^[36]. However, several studies highlighted that while BCAA supplementation reduced hepatic triglycerides, body weight, and food intake, hepatic IR could not be improved and a persistent induction of mTORC1 activation was observed, implying that the supplementation of BCAAs worsens the underlying metabolic disorder ^[37]^[38]^[39]. The persistent mTOR activation arose from the combination of both high-fat and BCAA supplementation, and this IR could be reversed using the mTORC1 inhibitor, rapamycin ^[14]. In contrast, rapamycin could not reverse high-fat diet-induced IR. Furthermore, BCAA-supplemented normal chow-feeding in rats did not induce increased mTOR activation ^[14]. This indicates that BCAA-high-fat-induced IR is likely to be more reversible compared to only high-fat-induced IR upon adopting a healthier diet. Furthermore, a previous survey conducted on the typical human Western diet found that the diet only contains around ~35% fat; hence, a review article suggested the use of diets with ~45% fat in rodents to confer a better rodent and human inter-study agreement ^[38]. Contradictory observations were found in the studies by Muyyarikkandy et al. and Zhao et al., who adopted a 60% fat rodent diet; thus, these observations may not necessarily be duplicated in humans. Indeed, a clinical trial of 102 NAFLD patients found that BCAA supplementation significantly lowered both liver disease markers (i.e., ALT and keratin-18 (K18)) and fibrosis markers ^[40]. With this, and the abundant evidence that BCAAs could help in liver cirrhosis, it should not be of great concern that BCAAs may exacerbate the disease condition if a healthy balanced diet is adopted during the intervention. On the other hand, the overall impression of these studies highlights the complex relationship between diet, BCAA, liver health, and IR, while also bringing attention to the gut–liver axis.

The full mechanism of how BCAAs prevent further deterioration in chronic liver diseases remains largely unclear. An explanation for this may be that the supplementation of BCAAs could elevate its catabolism via directly affecting the levels of its catabolizing enzyme. In particular, the increase in PPAR-α expression by BCAAs, through AMPK and an increase in serum-free fatty acid levels, could prevent the increase in BCKDK activity, preventing the suppression of BCKDH activity in catabolizing BCKAs ^[41]^[42]. The contribution of PPAR-α to lipid homeostasis was found to be crucial to preventing steatosis-induced NASH development ^[43]. It is also important to note that the loss of muscle mass, the major BCAA catabolic site, is usually accompanied by chronic liver diseases ^[44]^[45]. Improving the muscle mass ^[46] could potentially benefit muscle BCAA catabolism and its subsequent glutamine synthesis. The increase in plasma glutamine (GLN) was observed via the supplementation of BCAAs, along with a lowering of plasma glutamate (GLU) ^[47]. This increase in GLN availability was found to be beneficial to the immune system and the production of the natural antioxidant glutathione, which is beneficial to liver health ^[48]^[49].

References

Berg, E.H.V.D.; Flores-Guerrero, J.L.; Gruppen, E.G.; de Borst, M.H.; Wolak-Dinsmore, J.; Connelly, M.A.; Bakker, S.J.L.; Dullaart, R.P.F. Non-Alcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: Role of Circulating Branched-Chain Amino Acids. Nutrients 2019, 11, 705.
Borggreve, S.E.; Hillege, H.L.; Wolffenbuttel, B.H.R.; de Jong, P.E.; Bakker, S.J.L.; van der Steege, G.; van Tol, A.; Dullaart, R.P.F.; PREVEND Study Group. The effect of cholesteryl ester transfer protein -629C->A promoter polymorphism on high-density lipoprotein cholesterol is dependent on serum triglycerides. J. Clin. Endocrinol. Metab. 2005, 90, 4198–4204.
Chashmniam, S.; Ghafourpour, M.; Farimani, A.R.; Gholami, A.; Ghoochani, B.F.N.M. Metabolomic Biomarkers in the Diagnosis of Non-Alcoholic Fatty Liver Disease. Zahedan J. Res. Med Sci. 2019, 19.
Bhupathiraju, S.N.; Guasch-Ferré, M.; Gadgil, M.D.; Newgard, C.B.; Bain, J.R.; Muehlbauer, M.J.; Ilkayeva, O.R.; Scholtens, D.M.; Hu, F.B.; Kanaya, A.M.; et al. Dietary Patterns among Asian Indians Living in the United States Have Distinct Metabolomic Profiles That Are Associated with Cardiometabolic Risk. J. Nutr. 2018, 148, 1150–1159.
Männistö, V.T.; Simonen, M.; Hyysalo, J.; Soininen, P.; Kangas, A.; Kaminska, D.; Matte, A.K.; Venesmaa, S.; Käkelä, P.; Kärjä, V.; et al. Ketone body production is differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans. Liver Int. 2014, 35, 1853–1861.
Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016, 64, 73–84.
Tobias, D.K.; Clish, C.; Mora, S.; Li, J.; Liang, L.; Hu, F.B.; Manson, J.E.; Zhang, C. Dietary Intakes and Circulating Concentrations of Branched-Chain Amino Acids in Relation to Incident Type 2 Diabetes Risk Among High-Risk Women with a History of Gestational Diabetes Mellitus. Clin. Chem. 2018, 64, 1203–1210.
Sjögren, R.J.O.; Rizo-Roca, D.; Chibalin, A.V.; Chorell, E.; Furrer, R.; Katayama, S.; Harada, J.; Karlsson, H.K.R.; Handschin, C.; Moritz, T.; et al. Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes. Diabetologia 2021, 64, 2077–2091.
Gaggini, M.; Carli, F.; Bugianesi, E.; Gastaldelli, A.; Rosso, C.; Buzzigoli, E.; Marietti, M.; Della Latta, V.; Ciociaro, D.; Abate, M.L.; et al. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. Hepatology 2018, 67, 145–158.
Lischka, J.; Schanzer, A.; Hojreh, A.; Ssalamah, A.B.; Item, C.B.; de Gier, C.; Walleczek, N.; Metz, T.F.; Jakober, I.; Greber-Platzer, S.; et al. A branched-chain amino acid-based metabolic score can predict liver fat in children and adolescents with severe obesity. Pediatr. Obes. 2020, 16, e12739.
Feldman, A.; Eder, S.; Felder, T.; Paulweber, B.; Zandanell, S.; Stechemesser, L.; Schranz, M.; Strebinger, G.; Huber-Schönauer, U.; Niederseer, D.; et al. Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach. Diabetes Metab. 2018, 45, 132–139.
Galarregui, C.; Cantero, I.; Marin-Alejandre, B.A.; Monreal, J.I.; Elorz, M.; Benito-Boillos, A.; Herrero, J.I.; de la O, V.; Ruiz-Canela, M.; Hermsdorff, H.H.M.; et al. Dietary intake of specific amino acids and liver status in subjects with nonalcoholic fatty liver disease: Fatty liver in obesity (FLiO) study. Eur. J. Nutr. 2020, 60, 1769–1780.
Hasegawa, T.; Iino, C.; Endo, T.; Mikami, K.; Kimura, M.; Sawada, N.; Nakaji, S.; Fukuda, S. Changed Amino Acids in NAFLD and Liver Fibrosis: A Large Cross-Sectional Study without Influence of Insulin Resistance. Nutrients 2020, 12, 1450.
Newgard, C.B.; An, J.; Bain, J.R.; Muehlbauer, M.J.; Stevens, R.D.; Lien, L.F.; Haqq, A.M.; Shah, S.H.; Arlotto, M.; Slentz, C.A.; et al. A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance. Cell Metab. 2009, 9, 311–326.
Weickert, M.O.; Roden, M.; Isken, F.; Hoffmann, D.; Nowotny, P.; Osterhoff, M.; Blaut, M.; Alpert, C.; Gögebakan, O.; Bumke-Vogt, C.; et al. Effects of supplemented isoenergetic diets differing in cereal fiber and protein content on insulin sensitivity in overweight humans. Am. J. Clin. Nutr. 2011, 94, 459–471.
Grzych, G.; Vonghia, L.; Bout, M.-A.; Weyler, J.; Verrijken, A.; Dirinck, E.; Curt, M.J.C.; Van Gaal, L.; Paumelle, R.; Francque, S.; et al. Plasma BCAA Changes in Patients With NAFLD Are Sex Dependent. J. Clin. Endocrinol. Metab. 2020, 105, 2311–2321.
Lake, A.D.; Novak, P.; Shipkova, P.; Aranibar, N.; Robertson, D.G.; Reily, M.D.; Lehman-McKeeman, L.D.; Vaillancourt, R.R.; Cherrington, N.J. Branched chain amino acid metabolism profiles in progressive human nonalcoholic fatty liver disease. Amino Acids 2015, 47, 603–615.
Zhenyukh, O.; Civantos, E.; Ruiz-Ortega, M.; Sánchez, M.S.; Vázquez, C.; Peiró, C.; Egido, J.; Mas, S. High concentration of branched-chain amino acids promotes oxidative stress, inflammation and migration of human peripheral blood mononuclear cells via mTORC1 activation. Free Radic. Biol. Med. 2017, 104, 165–177.
Ranjbar, M.R.N.; Luo, Y.; Di Poto, C.; Varghese, R.S.; Ferrarini, A.; Zhang, C.; Sarhan, N.I.; Soliman, H.; Tadesse, M.G.; Ziada, D.H.; et al. GC-MS Based Plasma Metabolomics for Identification of Candidate Biomarkers for Hepatocellular Carcinoma in Egyptian Cohort. PLoS ONE 2015, 10, e0127299.
Hiraoka, A.; Kato, M.; Marui, K.; Murakami, T.; Onishi, K.; Adachi, T.; Matsuoka, J.; Ueki, H.; Yoshino, T.; Tsuruta, M.; et al. Easy clinical predictor for low BCAA to tyrosine ratio in chronic liver disease patients with hepatocellular carcinoma: Usefulness of ALBI score as nutritional prognostic marker. Cancer Med. 2021, 10, 3584–3592.
Tada, T.; Kumada, T.; Toyoda, H.; Kiriyama, S.; Tanikawa, M.; Hisanaga, Y.; Kanamori, A.; Kitabatake, S.; Yama, T. Impact of the branched-chain amino acid to tyrosine ratio and branched-chain amino acid granule therapy in patients with hepatocellular carcinoma: A propensity score analysis. J. Gastroenterol. Hepatol. 2015, 30, 1412–1419.
Buchard, B.; Teilhet, C.; Samarakoon, N.A.; Massoulier, S.; Joubert-Zakeyh, J.; Blouin, C.; Reynes, C.; Sabatier, R.; Biesse-Martin, A.-S.; Vasson, M.-P.; et al. Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity. Metabolites 2021, 11, 54.
Ericksen, R.E.; Lim, S.L.; McDonnell, E.; Shuen, W.H.; Vadiveloo, M.; White, P.J.; Ding, Z.; Kwok, R.; Lee, P.; Radda, G.K.; et al. Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression. Cell Metab. 2019, 29, 1151–1165.e6.
Biswas, D.; Duffley, L.; Pulinilkunnil, T. Role of branched-chain amino acid–catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis. FASEB J. 2019, 33, 8711–8731.
Wang, J.; Liu, Y.; Lian, K.; Shentu, X.; Fang, J.; Shao, J.; Chen, M.; Wang, Y.; Zhou, M.; Sun, H. BCAA Catabolic Defect Alters Glucose Metabolism in Lean Mice. Front. Physiol. 2019, 10, 1140.
Vilstrup, H.; Amodio, P.; Bajaj, J.; Cordoba, J.; Ferenci, P.; Mullen, K.D.; Weissenborn, K.; Wong, P. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014, 60, 715–735.
Gil Park, J.; Tak, W.Y.; Park, S.Y.; Kweon, Y.O.; Chung, W.J.; Jang, B.K.; Bae, S.H.; Lee, H.J.; Jang, J.Y.; Suk, K.T.; et al. Effects of Branched-Chain Amino Acid (BCAA) Supplementation on the Progression of Advanced Liver Disease: A Korean Nationwide, Multicenter, Prospective, Observational, Cohort Study. Nutrients 2020, 12, 1429.
Marchesini, G.; Bianchi, G.; Merli, M.; Amodio, P.; Panella, C.; Loguercio, C.; Fanelli, F.R.; Abbiati, R. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: A double-blind, randomized trial. Gastroenterology 2003, 124, 1792–1801.
Nojiri, S.; Fujiwara, K.; Shinkai, N.; Iio, E.; Joh, T. Effects of branched-chain amino acid supplementation after radiofrequency ablation for hepatocellular carcinoma: A randomized trial. Nutrition 2016, 33, 20–27.
Hayaishi, S.; Chung, H.; Kudo, M.; Ishikawa, E.; Takita, M.; Ueda, T.; Kitai, S.; Inoue, T.; Yada, N.; Hagiwara, S.; et al. Oral Branched-Chain Amino Acid Granules Reduce the Incidence of Hepatocellular Carcinoma and Improve Event-Free Survival in Patients with Liver Cirrhosis. Dig. Dis. 2011, 29, 326–332.
Simonetti, R.G.; Fiorello, F.; Politi, F.; D’Amico, G.; Pagliaro, L. Hepatocellular carcinoma. Am. J. Dig. Dis. 1991, 36, 962–972.
Cha, J.H.; Bae, S.H.; Kim, H.L.; Park, N.R.; Choi, E.S.; Jung, E.S.; Choi, J.Y.; Yoon, S.K. Branched-Chain Amino Acids Ameliorate Fibrosis and Suppress Tumor Growth in a Rat Model of Hepatocellular Carcinoma with Liver Cirrhosis. PLoS ONE 2013, 8, e77899.
Luo, L.; Sun, W.; Zhu, W.; Li, S.; Zhang, W.; Xu, X.; Fang, D.; Grahn, T.H.M.; Jiang, L.; Zheng, Y. BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism. Cell Death Dis. 2021, 12, 1–13.
Honda, T.; Ishigami, M.; Luo, F.; Lingyun, M.; Ishizu, Y.; Kuzuya, T.; Hayashi, K.; Nakano, I.; Ishikawa, T.; Feng, G.-G.; et al. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice. Metabolism 2017, 69, 177–187.
Arakawa, M.; Masaki, T.; Nishimura, J.; Seike, M.; Yoshimatsu, H. The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice. Endocr. J. 2011, 58, 161–170.
Iwao, M.; Gotoh, K.; Arakawa, M.; Endo, M.; Honda, K.; Seike, M.; Murakami, K.; Shibata, H. Supplementation of branched-chain amino acids decreases fat accumulation in the liver through intestinal microbiota-mediated production of acetic acid. Sci. Rep. 2020, 10, 1–11.
Hoyles, L.; Fernández-Real, J.-M.; Federici, M.; Serino, M.; Abbott, J.; Charpentier, J.; Heymes, C.; Luque, J.L.; Anthony, E.; Barton, R.H.; et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 2018, 24, 1070–1080.
Zhao, H.; Zhang, F.; Sun, D.; Wang, X.; Zhang, X.; Zhang, J.; Yan, F.; Huang, C.; Xie, H.; Lin, C.; et al. Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling. Diabetes 2020, 69, 1164–1177.
Muyyarikkandy, M.S.; McLeod, M.; Maguire, M.; Mahar, R.; Kattapuram, N.; Zhang, C.; Surugihalli, C.; Muralidaran, V.; Vavilikolanu, K.; Mathews, C.E.; et al. Branched chain amino acids and carbohydrate restriction exacerbate ketogenesis and hepatic mitochondrial oxidative dysfunction during NAFLD. FASEB J. 2020, 34, 14832–14849.
Harrison, S.A.; Baum, S.J.; Gunn, N.T.; Younes, Z.H.; Kohli, A.; Patil, R.; Koziel, M.J.; Chera, H.; Zhao, J.; Chakravarthy, M.V. Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease. Am. J. Gastroenterol. 2021, 116, 2399–2409.
Nishimura, J.; Masaki, T.; Arakawa, M.; Seike, M.; Yoshimatsu, H. Isoleucine Prevents the Accumulation of Tissue Triglycerides and Upregulates the Expression of PPARα and Uncoupling Protein in Diet-Induced Obese Mice. J. Nutr. 2010, 140, 496–500.
Burri, L.; Thoresen, G.H.; Berge, R.K. The Role of PPARαActivation in Liver and Muscle. PPAR Res. 2010, 2010, 1–11.
Regnier, M.; Polizzi, A.; Smati, S.; Lukowicz, C.; Fougerat, A.; Lippi, Y.; Fouché, E.; Lasserre, F.; Naylies, C.; Bétoulières, C.; et al. Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity. Sci. Rep. 2020, 10, 1–15.
Lee, J.-H.; Lee, H.-S.; Lee, B.-K.; Kwon, Y.-J.; Lee, J.-W. Relationship between Muscle Mass and Non-Alcoholic Fatty Liver Disease. Biology 2021, 10, 122.
Cai, C.; Song, X.; Chen, Y.; Chen, X.; Yu, C. Relationship between relative skeletal muscle mass and nonalcoholic fatty liver disease: A systematic review and meta-analysis. Hepatol. Int. 2019, 14, 115–126.
Tejavath, A.S.; Mathur, A.; Nathiya, D.; Singh, P.; Raj, P.; Suman, S.; Mundada, P.R.; Atif, S.; Rai, R.R.; Tomar, B.S. Impact of Branched Chain Amino Acid on Muscle Mass, Muscle Strength, Physical Performance, Combined Survival, and Maintenance of Liver Function Changes in Laboratory and Prognostic Markers on Sarcopenic Patients With Liver Cirrhosis (BCAAS Study): A Randomized Clinical Trial. Front. Nutr. 2021, 8.
Holecek, M.; Siman, P.; Vodenicarovova, M.; Kandar, R. Alterations in protein and amino acid metabolism in rats fed a branched-chain amino acid- or leucine-enriched diet during postprandial and postabsorptive states. Nutr. Metab. 2016, 13, 12.
Cruzat, V.; Macedo Rogero, M.; Keane, K.N.; Curi, R.; Newsholme, P. Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients 2018, 10, 1564.
Honda, Y.; Kessoku, T.; Sumida, Y.; Kobayashi, T.; Kato, T.; Ogawa, Y.; Tomeno, W.; Imajo, K.; Fujita, K.; Yoneda, M.; et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: An open-label, single-arm, multicenter, pilot study. BMC Gastroenterol. 2017, 17, 1–8.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Biochemistry & Molecular Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Emily Kwun Kwan Lo

Felicianna

Jing-Hang Xu

Qiao Zhan

Zheng Zeng

Hani El-Nezami

View Times: 490

Update Date: 30 Jun 2022

Table of Contents

Video Upload Options

Confirm