Branched-chain amino acids and l-carnitine attenuate lipotoxic hepatocellular damage in rat cirrhotic liver

Tamai, Youichi; Chen, Zhen; Wu, Yue; Okabe, Jun; Kobayashi, Yoshinao; Chiba, Hitoshi; Hui, Shu‐Ping; Iwasa, Motoh; M, Ito; Takei, Yoshiyuki

doi:10.1016/j.biopha.2020.111181

Cited by 14 publications

(13 citation statements)

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“…Electronic address and European Association for the Study of the, 2019), as well as increased muscle mass associated with an acceleration of the TCA cycle (Ismaiel et al, 2022). In our previous study, we reported that hepatocellular damage was attenuated using BCAA supplementation as a result of improved lipid metabolism and mitochondrial damage repair in CLD rats (Tamai et al, 2021). Using the same CLD rat model in the current study, we revealed that gastrocnemius muscle mass was significantly increased using BCAA treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Our animal protocol (HKD43046) was reviewed and approved by the Institutional Animal Care and Use Committee at Hokudo Co., Ltd (Sapporo, Japan). The rat model of CLD has been previously described in detail (Tamai et al, 2021). Briefly, Wister male rats (SPF, CLEA Japan: Tokyo, Japan) aged 7 weeks were fed solid normal diet, CE-2 (CLEA Japan), under conventional conditions and were orally administered CCl 4 at 1.0 mL/kg twice a week for 4 weeks to induce advanced fibrosis, or cirrhosis, at which point the animals were divided into 2 groups by weight stratified random sampling.…”

Section: Methodsmentioning

confidence: 99%

“…To investigate whether increased gastrocnemius muscle weight is associated with changes in BA composition, we used a CLD rat model administered with carbontetrachloride (CCl 4 ) for 10 weeks (4 weeks to establish advanced fibrosis, or cirrhosis, and an additional 6 weeks to treat with BCAA for attenuation of liver injury), which we have previously reported (Tamai et al, 2021). The ratio of gastrocnemius muscle weight to total body weight was significantly increased in CLD rats treated with BCAA (CLD+BCAA) compared to untreated CLD rats (p <0.05) (Figure . 1A).…”

Section: Bcaamentioning

confidence: 99%

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Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in chronic liver disease rats and humans

Tamai

Shigefuku

Kitamura

et al. 2022

Preprint

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[Background] Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate, however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition. <br />[Methods] Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy. The correlation between serum BA levels and psoas muscle area index (PMI) was examined in 113 CLD patients. <br />[Results] Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist. In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. <br />[Conclusion] Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival. <br />[Funding] This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Bcaamentioning

confidence: 99%

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Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in chronic liver disease rats and humans

Tamai

Shigefuku

Kitamura

et al. 2022

Preprint

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“…64 Research on BCAAs oral supplementation has shown decreased fat accumulation in the liver and attenuation of lipotoxic hepatocellular damage in the cirrhotic liver. [65][66][67][68][69] However, several reports revealed that the elevated circulating BCAA was associated with MAFLD and liver injury. 70,71 BCAAs (including valine, leucine, & isoleucine) were found to increase during MAFLD progression as a response to the increased inflammation and oxidative stress.…”

Section: Branched-chain and Aromatic Amino Acids And Metabolic-associated Fatty Liver Diseasementioning

confidence: 99%

The microbial metabolome in metabolic‐associated fatty liver disease

Rajani

Zheng

et al. 2021

J of Gastro and Hepatol

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Metabolism-associated fatty liver disease (MAFLD) is defined as the presence of excess fat in the liver in the absence of excess alcohol consumption and metabolic dysfunction. It has also been described as the hepatic manifestation of metabolic syndrome. The incidence of MAFLD has been reported to be 43-60% in diabetics, ~90% in patients with hyperlipidemia, and 91% in morbidly obese patients. Risk factors that have been associated with the development of MAFLD include male gender, increasing age, obesity, insulin resistance, diabetes, and hyperlipidemia. All of these risk factors have been linked to alterations of the gut microbiota, that is, gut dysbiosis. MAFLD can progress to non-alcoholic steatohepatitis with the presence of inflammation and ballooning, which can deteriorate into cirrhosis, MAFLD-related hepatocellular carcinoma, and liver failure. In this review, we will be focused on the role of the gut microbial metabolome in the development, progression, and potential treatment of MAFLD.

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“…They belong to the group of essential amino acids, which in animals are only present in small amounts. Aberrant BCAA homeostasis has been observed in a number of disorders, such as type 2 diabetes, liver cirrhosis, renal failure, and cancer (6)(7)(8)(9). They present diverse biological functions in the pathogenesis of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Aberrant branched-chain amino acid catabolism in cardiovascular diseases

Xiong

Jiang

2022

Front. Cardiovasc. Med.

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Globally, cardiovascular diseases are the leading cause of death. Research has focused on the metabolism of carbohydrates, fatty acids, and amino acids to improve the prognosis of cardiovascular diseases. There are three types of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) required for protein homeostasis, energy balance, and signaling pathways. Increasing evidence has implicated BCAAs in the pathogenesis of multiple cardiovascular diseases. This review summarizes the biological origin, signal transduction pathways and function of BCAAs as well as their significance in cardiovascular diseases, including myocardial hypertrophy, heart failure, coronary artery disease, diabetic cardiomyopathy, dilated cardiomyopathy, arrhythmia and hypertension.

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Branched-chain amino acids and l-carnitine attenuate lipotoxic hepatocellular damage in rat cirrhotic liver

Cited by 14 publications

References 54 publications

Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in chronic liver disease rats and humans

Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in chronic liver disease rats and humans

The microbial metabolome in metabolic‐associated fatty liver disease

Aberrant branched-chain amino acid catabolism in cardiovascular diseases

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