Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway - potential implications for nonalcoholic fatty liver disease

Zarfeshani, Aida; Ngo, Sherry; Sheppard, Allan

doi:10.1186/1868-7083-6-27

Cited by 27 publications

(27 citation statements)

References 52 publications

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“…And while this study did not observe changes in mTORc1 activation, leucine treatment resulted in heightened lipogenic gene expression including elevated Pparg, glycerol-3-phosphate acyl transferase 1 (Gpat1), and acetyl-CoA carboxylase 1 (Acaca1), as well as metabolic transcription factors Ppargc-1 and FoxO1 expression (Zarfeshani et al, 2014). The same report also showed increased intracellular triacylglycerol content of leucinetreated cells, which was associated with elevated glucose uptake (Zarfeshani et al, 2014). Past reports have also investigated the effect of concurrent leucine and palmitate treatment on myotube metabolism.…”

Section: Discussioncontrasting

confidence: 70%

“…Additionally, leucine is a known activator of mTOR that is a regulator of PPARγ and SREBP‐1c (Laplante and Sabatini, ), targets that may represent a potential mechanism by which leucine increases lipid content (however these and other potential mechanism require additional study). One such example was demonstrated using cultured hepatocytes treated with leucine at either 0.1 or 2.5 mM (Zarfeshani et al, ). And while this study did not observe changes in mTORc1 activation, leucine treatment resulted in heightened lipogenic gene expression including elevated Pparg , glycerol‐3‐phosphate acyl transferase 1 ( Gpat1 ), and acetyl‐CoA carboxylase 1 ( Acaca1 ), as well as metabolic transcription factors Ppargc‐1 and FoxO1 expression (Zarfeshani et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Leucine, Palmitate, or Leucine/Palmitate Cotreatment Enhances Myotube Lipid Content and Oxidative Preference

Johnson

Gannon

Schnuck

et al. 2018

Lipids

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Branched‐chain amino acids (BCAA) such as leucine stimulate favorable metabolic processes involved in lean tissue preservation and skeletal muscle metabolism. However, higher levels of circulating BCAA correlate with severity of metabolic disease (including diabetes/insulin resistance), and may result from dysregulated BCAA catabolism. Past observations have demonstrated potential interaction between BCAA and dietary fat; however, much of this relationship remains underexplored. This study investigated the effect of leucine both with and without palmitate on oxidative and glycolytic metabolism, as well as indicators of BCAA catabolism using cultured skeletal muscle cells. Specifically, C2C12 myotubes were treated with or without varying concentrations of leucine both with and without palmitate for 24 h. Leucine treatment significantly elevated mRNA expression of metabolic regulators including peroxisome proliferator‐activated receptor‐gamma coactivator 1‐alpha versus leucine with concurrent palmitate treatment. Interestingly, leucine‐only, palmitate‐only, and leucine with palmitate all significantly increased cellular lipid content, which translated into significantly increased oxidative capacity under substrate‐limited conditions. However, upon the addition of excess substrate and carnitine, discrepancies in peak metabolic capacities between various treatments were no longer observed, suggesting leucine, palmitate, or the combination thereof causes a shift in metabolic preference from glycolytic to oxidative. These data also suggest leucine's effect on mitochondrial metabolism may result in part from increased lipid stores in addition to other previously documented pathways.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Leucine, Palmitate, or Leucine/Palmitate Cotreatment Enhances Myotube Lipid Content and Oxidative Preference

Johnson

Gannon

Schnuck

et al. 2018

Lipids

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“…3A). Given that myostatin, another molecule that is involved in muscle atrophy, is counteracted by decorin [25,27,37] and is closely associated with AMPK-mediated energy metabolism and atrophy [38][39][40][41], we evaluated the expression of myostatin in inflamed C2C12 myotubes. We found that the expression levels of myostatin and MAFbx in C2C12 myotubes was significantly increased, while the levels of decorin, MyoD, and myogenin were significantly decreased after treatment with a cytokine mixture for 24 h (Fig.…”

Section: Effects Of Inflammation On Myoblast Differentiation and Myokmentioning

confidence: 99%

Roles of Exosome-Like Vesicles Released from Inflammatory C2C12 Myotubes: Regulation of Myocyte Differentiation and Myokine Expression

Kim

Lee

Choi

et al. 2018

Cell Physiol Biochem

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Background/Aims: The complicated differentiation processes of cells in skeletal muscle against inflammation that induce muscle atrophy are not fully elucidated. Given that skeletal muscle is a secretory organ, we evaluated the effects of inflammation on myogenic signals and myokine expression, and the roles of inflammatory exosomes released by myotubes in myogenic differentiation. Methods: Inflammation was induced by treatment of fully differentiated C2C12 myotubes with a cytokine mixture of TNF-α and INF-γ. Exosome-like vesicles (ELVs) were isolated from conditioned media of control or inflamed myotubes and incubated with myoblasts. The expression of molecular switches that contribute to myogenic differentiation, including several kinases, their downstream targets, and myokines, were evaluated using immunoblot analysis in inflamed myotubes and in myoblasts treated with ELVs. Results: Inflammation activated molecular mechanisms contributing to muscle atrophy, including AMPK, p-38 MAPK and JNK, while inhibiting Akt-mediated myogenic signals. In addition, inflammation induced myostatin expression with suppression of a myostatin-counteracting myokine, decorin. Well-characterized ELVs released from inflamed myotubes induced myoblast inflammation and inhibited myogenic mechanisms while stimulating atrophic signals. Conclusion: Inflammation of skeletal muscle induces muscle atrophy via multiple mechanisms, including the regulation of myokines and kinases. Inflammatory ELVs are likely to contribute to inflammation-induced muscle atrophy.

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“…LRP and LQP contain leucine, a branched-chain amino acid, which regulates lipid metabolism via the AMPK signaling pathway (21). Therefore, we evaluated the effects of LRP and LQP on phosphorylation of AMPK and ACC, a downstream lipogenic molecule of AMPK.…”

Section: Discussionmentioning

confidence: 99%

“…These peptides inhibit angiotensin I-converting enzyme (ACE), which causes oxidative stress (19,20). In addition, these peptides contain leucine, a branched-chain amino acid, which regulates lipid metabolism via activation of the AMP-activated protein kinase (AMPK) signaling pathway (21). Since increased oxidative stress and downregulation of AMPK are major pathogenic factors of NASH, these wheat-bran autolytic peptides may be potent therapeutic supplements for the treatment of NASH.…”

Section: Introductionmentioning

confidence: 99%

Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice

Kawaguchi

Ueno

Nogata

et al. 2016

International Journal of Molecular Medicine

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Abstract. Whole-wheat intake is known to reduce the risk of metabolic syndrome. However, the active component remains unclear. Recently, we identified bioactive peptides [leucinearginine-proline (LRP) and leucine-glutamine-proline (LQP)] from wheat bran autolytic hydrolysate. The present study aimed to investigate the effects of LRP and LQP on non-alcoholic steatohepatitis (NASH) in a mouse model. We also evaluated the effects of these peptides on oxidative stress and on the AMP-activated protein kinase (AMPK) signaling pathway, two major pathogenic factors of NASH. Seven-week-old male C57BL/6 mice were fed a high-fat diet for 10 weeks and administered water supplemented with 0.05% LRP, 0.20% LRP, 0.05% LQP, or 0.20% LQP (each n=5) or distilled water (control; n=5) ad libitum. Oxidative stress was evaluated by measuring the serum levels of diacron reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP). Hepatic expression of phosphorylated AMPK and phosphorylated acetyl-CoA carboxylase (ACC) were evaluated by immunoblotting. The result showed that non-alcoholic fatty liver disease activity score was significantly decreased in all types of treatment. Serum d-ROM levels were significantly decreased in the 0.20% LRP group, but not in the 0.05% LRP, 0.05% LQP, and 0.20% LQP groups. Serum BAP levels were significantly increased in the 0.05% LRP and 0.20% LRP groups, but not in the 0.05% LQP and 0.20% LQP groups. Immunoblotting analysis revealed that the expression of phospho-AMPK was increased whereas that of phospho-ACC was decreased in the 0.20% LQP group. In conclusion, we demonstrated that both LRP and LQP alleviated the severity of NASH in a high-fat diet-induced NASH mouse model. In addition, we showed that LRP and LQP modulated oxidative stress and upregulated AMPK/ACC, respectively. Thus, LRP and LQP may constitute clinically applicable therapeutic agents for NASH. IntroductionNon-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. The prevalence of NAFLD is estimated to range from 25 to 37% of the general population (1-4), and it constitutes a common etiological factor of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD. Patients with NASH have a high risk of life-threatening complications, including cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma (5,6). In addition, NASH is predicted to become the leading cause of liver transplantation in the USA by the year 2020 (2). Thus, NAFLD/NASH is becoming a major social issue worldwide.The first-line therapy for NASH is life-style intervention. Although diet and exercise alleviate the severity of NASH, long-term adherence to life-style interventions is poor (7,8). Pioglitazone, an insulin-sensitizing anti-diabetic agent, leads to metabolic and histologic improvement in patients with NASH (9). However, the indication of pioglitazone is restricted to NASH patients with diabetes mellitus (10). Furthermore, severe liver disease is a contrai...

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Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway - potential implications for nonalcoholic fatty liver disease

Cited by 27 publications

References 52 publications

Leucine, Palmitate, or Leucine/Palmitate Cotreatment Enhances Myotube Lipid Content and Oxidative Preference

Leucine, Palmitate, or Leucine/Palmitate Cotreatment Enhances Myotube Lipid Content and Oxidative Preference

Roles of Exosome-Like Vesicles Released from Inflammatory C2C12 Myotubes: Regulation of Myocyte Differentiation and Myokine Expression

Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice

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