Nejvíce citovaný článek - PubMed ID 28760433
Branched-chain amino acid supplementation in treatment of liver cirrhosis: Updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation
Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.
- Klíčová slova
- Aging, Hepatic stellate cells, Hepatocytes, Liver, Metabolomics, SIRT6, Spheroids,
- MeSH
- hepatocelulární karcinom * metabolismus patologie MeSH
- hepatocyty metabolismus patologie MeSH
- kolagen metabolismus MeSH
- lidé MeSH
- nádory jater * metabolismus patologie MeSH
- nealkoholová steatóza jater * genetika metabolismus patologie MeSH
- senioři nad 80 let MeSH
- sirtuiny * genetika metabolismus MeSH
- století lidé MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kolagen MeSH
- SIRT6 protein, human MeSH Prohlížeč
- sirtuiny * MeSH
The aim of the article is to examine side effects of increased dietary intake of amino acids, which are commonly used as a dietary supplement. In addition to toxicity, mutagenicity and carcinogenicity, attention is focused on renal and gastrointestinal tract functions, ammonia production, and consequences of a competition with other amino acids for a carrier at the cell membranes and enzymes responsible for their degradation. In alphabetic order are examined arginine, beta-alanine, branched-chain amino acids, carnosine, citrulline, creatine, glutamine, histidine, beta -hydroxy- beta -methylbutyrate, leucine, and tryptophan. In the article is shown that enhanced intake of most amino acid supplements may not be risk-free and can cause a number of detrimental side effects. Further research is necessary to elucidate effects of high doses and long-term consumption of amino acid supplements on immune system, brain function, muscle protein balance, synthesis of toxic metabolites, and tumor growth and examine their suitability under certain circumstances. These include elderly, childhood, pregnancy, nursing a baby, and medical condition, such as diabetes and liver disease. Studies are also needed to examine adaptive response to a long-term intake of any substance and consequences of discontinuation of supplementation.
- MeSH
- aminokyseliny škodlivé účinky metabolismus MeSH
- arginin farmakologie MeSH
- dítě MeSH
- glutamin * metabolismus farmakologie MeSH
- histidin metabolismus MeSH
- kosterní svaly metabolismus MeSH
- lidé MeSH
- potravní doplňky * škodlivé účinky MeSH
- senioři MeSH
- těhotenství MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- senioři MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminokyseliny MeSH
- arginin MeSH
- glutamin * MeSH
- histidin MeSH
In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements. It is hypothesized that, under hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions.
- Klíčová slova
- exercise, glutamine, liver cirrhosis, urea-cycle disorders, α-ketoglutarate,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The aim of the study was to examine whether a rat model of liver cirrhosis induced by carbon tetrachloride (CCl4) is a suitable model of muscle wasting and alterations in amino acid metabolism in cirrhotic humans. Rats were treated by intragastric gavage of CCl4 or vehicle for 45 days. Blood plasma and different muscle types-tibialis anterior (mostly white fibres), soleus (red muscle) and extensor digitorum longus (white muscle) - were analysed at the end of the study. Characteristic biomarkers of impaired hepatic function were found in the plasma of cirrhotic animals. The weights and protein contents of all muscles of CCl4-treated animals were lower when compared with controls. Increased concentrations of glutamine (GLN) and aromatic amino acids (phenylalanine and tyrosine) and decreased concentrations of branched-chain amino acids (BCAA), glutamate (GLU), alanine and aspartate were found in plasma and muscles. In the soleus muscle, GLN increased more and GLU and BCAA decreased less than in the extensor digitorum and tibialis muscles. Increased chymotrypsin-like activity (indicating enhanced proteolysis) and decreased α-ketoglutarate and ATP levels were found in muscles of cirrhotic animals. ATP concentration also decreased in blood plasma. It is concluded that a rat model of CCl4-induced cirrhosis is a valid model for the investigation of hepatic cachexia that exhibits alterations in line with a theory of role of ammonia in pathogenesis of BCAA depletion, citric cycle and mitochondria dysfunction, and muscle wasting in cirrhotic subjects. The findings indicate more effective ammonia detoxification to GLN in red than in white muscles.
- Klíčová slova
- ammonia detoxification, cachexia, glutamine, liver cirrhosis,
- MeSH
- adenosintrifosfát nedostatek MeSH
- chlorid uhličitý farmakologie MeSH
- jaterní cirhóza chemicky indukované komplikace metabolismus patologie MeSH
- kosterní svaly metabolismus patologie MeSH
- kyseliny ketoglutarové metabolismus MeSH
- modely nemocí na zvířatech MeSH
- potkani Wistar MeSH
- přijímání potravy účinky léků MeSH
- sarkopenie etiologie metabolismus patologie MeSH
- svalové proteiny metabolismus MeSH
- tělesná hmotnost účinky léků MeSH
- velikost orgánu účinky léků MeSH
- větvené aminokyseliny metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adenosintrifosfát MeSH
- chlorid uhličitý MeSH
- kyseliny ketoglutarové MeSH
- svalové proteiny MeSH
- větvené aminokyseliny MeSH
The aim was to determine the effects of enhanced availability of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) on ammonia detoxification to glutamine (GLN) and protein metabolism in two types of skeletal muscle under hyperammonemic conditions. Isolated soleus (SOL, slow-twitch) and extensor digitorum longus (EDL, fast-twitch) muscles from the left leg of white rats were incubated in a medium with 1 mM ammonia (NH3 group), BCAAs at four times the concentration of the controls (BCAA group) or high levels of both ammonia and BCAA (NH3 + BCAA group). The muscles from the right leg were incubated in basal medium and served as paired controls. L-[1-14C]leucine was used to estimate protein synthesis and leucine oxidation, and 3-methylhistidine release was used to evaluate myofibrillar protein breakdown. We observed decreased protein synthesis and glutamate and α-ketoglutarate (α-KG) levels and increased leucine oxidation, GLN levels, and GLN release into medium in muscles in NH3 group. Increased leucine oxidation, release of branched-chain keto acids and GLN into incubation medium, and protein synthesis in EDL were observed in muscles in the BCAA group. The addition of BCAAs to medium eliminated the adverse effects of ammonia on protein synthesis and adjusted the decrease in α-KG found in the NH3 group. We conclude that (i) high levels of ammonia impair protein synthesis, activate BCAA catabolism, enhance GLN synthesis, and decrease glutamate and α-KG levels and (ii) increased BCAA availability enhances GLN release from muscles and attenuates the adverse effects of ammonia on protein synthesis and decrease in α-KG.
- Klíčová slova
- Ammonia, Branched-chain amino acids, Glutamine, Ketoglutarate, Liver cirrhosis,
- MeSH
- amoniak otrava MeSH
- citrátový cyklus účinky léků MeSH
- glutamin agonisté metabolismus MeSH
- hyperamonemie enzymologie metabolismus patofyziologie MeSH
- jaterní cirhóza etiologie metabolismus MeSH
- kyseliny ketoglutarové metabolismus MeSH
- methylhistidiny metabolismus MeSH
- orgánová specificita MeSH
- osmolární koncentrace MeSH
- oxidace-redukce MeSH
- potkani Wistar MeSH
- proteolýza účinky léků MeSH
- proteosyntéza účinky léků MeSH
- radioizotopy uhlíku MeSH
- svalová vlákna typu I účinky léků enzymologie metabolismus MeSH
- svalová vlákna typu II účinky léků enzymologie metabolismus MeSH
- svalové proteiny genetika metabolismus MeSH
- techniky in vitro MeSH
- větvené aminokyseliny metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Názvy látek
- 3-methylhistidine MeSH Prohlížeč
- amoniak MeSH
- glutamin MeSH
- kyseliny ketoglutarové MeSH
- methylhistidiny MeSH
- radioizotopy uhlíku MeSH
- svalové proteiny MeSH
- větvené aminokyseliny MeSH
Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications.
