Arginine and NASH – Do macrophages deliver the first hit?

Scheja, Ludger; Kluwe, Johannes

doi:10.1016/j.jhep.2014.11.001

Cited by 6 publications

(7 citation statements)

References 19 publications

(18 reference statements)

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“…Arginase1 expressed by M2 macrophages is a key marker that confers anti-inflammatory properties. The enzyme competes with pro-inflammatory nitric oxide synthetase (iNOS), marker of M1 macrophages, which induces oxidative stress 63 . Curcuminoids were found to reduce inflammatory markers, including TNF-α, C reactive protein and NFkB expression in the liver, while GIE showed only a moderate effect on these markers.…”

Section: Discussionmentioning

confidence: 99%

Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice

Majeed

Nagabhushanam

et al. 2020

Sci Rep

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Non-alcoholic steatohepatitis (NASH) is a progressive form of Non-alcoholic fatty liver disease (NAFLD), a chronic liver disease with a significant unmet clinical need. In this study, we examined the protective effects of Garcinia indica extract standardized to contain 20% w/w of Garcinol (GIE) and 95% Curcuminoids w/w from Curcuma longa (Curcuminoids) in a Stelic animal model (STAM) of NASH. The STAM mice developed steatosis, hepatocyte ballooning, and inflammation, which were significantly reduced by the combination of GIE and Curcuminoids, resulting in a lower NAFLD activity score. The treatment reduced fibrosis as observed by Sirius red staining, liver hydroxyproline content and mRnA levels of tGf-β and collagen in the liver. Immunostaining with alpha-smooth muscle actin (α SMA) revealed a significant reduction in hepatic stellate cells. Intriguingly, the combination regimen markedly decreased the mRNA levels of MCP1 and CRP and both mRNA and protein levels of TNF-α. NF-kB, reduced the hepatic and circulating FGF21 levels and altered the nonenzymatic (glutathione) and enzymatic antioxidant markers (Glutathione peroxidase, and superoxide dismutase). Our results suggest that the combination of GIE and Curcuminoids can reduce the severity of NASH by reducing steatosis, fibrosis, oxidative stress, and inflammation. The results suggest that the combinatorial regimen could be an effective supplement to prevent the progression of liver steatosis to inflammation and fibrosis in NASH. Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disorders 1,2. It includes the spectrum of liver disease, ranging from benign fatty liver to hepatocellular carcinoma. It is histologically further categorized into the nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL, as the early-stage disease shows the presence of excessive fat in the liver (hepatic steatosis) with no evidence of hepatocellular injury, while NASH is characterized by the accumulation of fat accompanied by infiltration of inflammatory cells and cellular damage, which can progress to cirrhosis, liver failure, and liver cancer 3. NASH is the hepatic manifestation of metabolic disorder and is closely associated with type 2 diabetes, obesity, insulin resistance anda systemic inflammatory state 4-8. Consequently, NASH patients have a higher risk of cardiovascular events and neoplasia, resulting in a higher rate of mortality 9,10. It is usually a silent disease with minimum symptoms, while weight loss, fatigue, and weakness develop as the disease progresses. Although the disease development and progression are still not well elucidated, the most accepted theory to explain the pathogenesis is "multiple-hits hypothesis". The initial hit leads to the development of simple steatosis, while liver cell inflammation and apoptosis are induced by secondary hits, leading to mitochondrial dysfunction, oxidative stress, lipid peroxidation, gut dysbiosis, and Kupffer cell activation, which finally results in NASH 11,12. Presence...

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Section: Discussionmentioning

confidence: 99%

Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice

Majeed

Nagabhushanam

et al. 2020

Sci Rep

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“…In the context of NAFLD and metabolic syndrome, the conversion of arginine to NO and citrulline by NOS and its conversion to ornithine and urea by arginases have been of special interest. Induction of iNOS is a hallmark of M1 macrophages with the consequent production of oxidative stress [117]. Arg-1 is a key marker of M2 macrophages and confers anti-inflammatory properties by substrate competition with iNOS and through other mechanisms; M2 KCs can promote apoptosis of M1 KCs by an arginase-dependent mechanism, limiting liver injury and NASH progression [108].…”

Section: Liver Tissue Inflammationmentioning

confidence: 99%

The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

Alisi

Carpino

Oliveira

et al. 2017

Mediators of Inflammation

152

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The obese phenotype is characterized by a state of chronic low-grade systemic inflammation that contributes to the development of comorbidities, including nonalcoholic fatty liver disease (NAFLD). In fact, NAFLD is often associated with adipocyte enlargement and consequent macrophage recruitment and inflammation. Macrophage polarization is often associated with the proinflammatory state in adipose tissue. In particular, an increase of M1 macrophages number or of M1/M2 ratio triggers the production and secretion of various proinflammatory signals (i.e., adipocytokines). Next, these inflammatory factors may reach the liver leading to local M1/M2 macrophage polarization and consequent onset of the histological damage characteristic of NAFLD. Thus, the role of macrophage polarization and inflammatory signals appears to be central for pathogenesis and progression of NAFLD, even if the heterogeneity of macrophages and molecular mechanisms that govern their phenotype switch remain incompletely understood. In this review, we discuss the role of adipose and liver tissue macrophage-mediated inflammation in experimental and human NAFLD. This focus is relevant because it may help researchers that approach clinical and experimental studies on this disease advancing the knowledge of mechanisms that could be targeted in order to revert NAFLD-related fibrosis.

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“…Arginine not only acts as a precursor in protein synthesis and the urea cycle but also acts as a precursor in the generation of polyamines and creatine and converted to ornithine by the enzyme arginase. However, arginase-deficient mice develop spontaneous steatohepatitis, and the condition is exacerbated by feeding them a high-fat diet, suggesting that ornithine accumulation has a negative impact on obesity . (5) Another study also found that ornithine, inositol, tyrosine, and glycine concentrations in mouse serum were positively correlated with obesity .…”

Section: Resultsmentioning

confidence: 99%

Torularhodin-Loaded Bilosomes Ameliorate Lipid Accumulation and Amino Acid Metabolism in Hypercholesterolemic Mice

Liu

Guo

Cheng

et al. 2023

J. Agric. Food Chem.

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Scope: Hypercholesterolemia is a cause of cardiovascular disease. Torularhodin is a carotenoid, and its entrapment in bilosomes helps to improve its bioavailability. Methods and results: The effects of torularhodin-loaded bilosomes on lipid accumulation, inflammatory response, and serum metabolic profiles in hypercholesterolemic ApoE−/− C57BL/6J mice were investigated by feeding a high-fat, high-cholesterol diet (HFHCD) for 20 weeks. At the same time, mice were gavaged with torularhodin-loaded bilosomes for 10 weeks. The results showed that torularhodin successfully alleviated weight gain and insulin resistance in mice and could also lower blood lipids. Meanwhile, torularhodin improved liver lipid accumulation in mice and modulated inflammatory factors in the "blood−liver−ileum." Nontargeted metabolomics revealed that torularhodin significantly increased the concentrations of L-tryptophan, glyceraldehyde, hypotaurine, pyrophosphate, and niacinamide in serum (p < 0.01). In addition, targeted amino acid metabolomics verification found that torularhodin promoted the metabolism of serum amino acids in mice, particularly for branched-chain amino acids, thereby helping to improve hypercholesterolemia in mice. Finally, interaction network bioinformatics was used to demonstrate that amino acid metabolism represented an important mechanism by which torularhodin improves lipid accumulation and inflammatory response in mice. Conclusions: Torularhodin can improve hypercholesterolemia in HFHCD-fed mice, thereby supporting the feasibility of its usage in food applications for cardiovascular disease prevention.

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Arginine and NASH – Do macrophages deliver the first hit?

Cited by 6 publications

References 19 publications

Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice

Novel Combinatorial Regimen of Garcinol and Curcuminoids for Non-alcoholic Steatohepatitis (NASH) in Mice

The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

Torularhodin-Loaded Bilosomes Ameliorate Lipid Accumulation and Amino Acid Metabolism in Hypercholesterolemic Mice

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