Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

Etienne, Quentin; Lebrun, Valérie; Komuta, Mina; Navez, B.; Thissen, Jean‐Paul; Leclercq, Isabelle; Lanthier, Nicolas

doi:10.3390/metabo12070625

Cited by 14 publications

(10 citation statements)

References 47 publications

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“…As previously reported ( 16 , 46 , 49 – 51 ), FOZ mice fed a HFD for 12 weeks are obese, and exhibit severe steatosis, inflammation and ballooning (mean NAS = 6, Figures 1A,B ) with only inconspicuous fibrosis ( Figures 1A,C ). Inflammation and fibrosis are confirmed by gene expression analysis (S1A).…”

Section: Resultssupporting

confidence: 84%

Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations

et al. 2022

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BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in the world. Progression toward non-alcoholic steatohepatitis (NASH) is associated with alterations of skeletal muscle. One plausible mechanism for altered muscle compartment in liver disease is changes in ammonia metabolism. In the present study, we explored the hypothesis that NASH-associated hyperammonemia drives muscle changes as well as liver disease progression.Materials and methodsIn Alms1-mutant mice (foz/foz) fed a 60% fat diet (HFD) for 12 weeks; we investigated hepatic and muscular ammonia detoxification efficiency. We then tested the effect of an 8 week-long supplementation with L-ornithine L-aspartate (LOLA), a known ammonia-lowering treatment, given after either 4 or 12 weeks of HFD for a preventive or a curative intervention, respectively. We monitored body composition, liver and muscle state by micro computed tomography (micro-CT) as well as muscle strength by four-limb grip test.ResultsAccording to previous studies, 12 weeks of HFD induced NASH in all foz/foz mice. Increase of hepatic ammonia production and alterations of urea cycle efficiency were observed, leading to hyperammonemia. Concomitantly mice developed marked myosteatosis. First signs of myopenia occurred after 20 weeks of diet. Early LOLA treatment given during NASH development, but not its administration in a curative regimen, efficiently prevented myosteatosis and muscle quality, but barely impacted liver disease or, surprisingly, ammonia detoxification.ConclusionOur study confirms the perturbation of hepatic ammonia detoxification pathways in NASH. Results from the interventional experiments suggest a direct beneficial impact of LOLA on skeletal muscle during NASH development, though it does not improve ammonia metabolism or liver disease.

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Section: Resultssupporting

confidence: 84%

Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations

et al. 2022

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“…Also, recent studies have shown some mechanisms of the relationship between fetuin-A and NAFLD. In particular, the study [9] showed that an increase in VAT leads to an excess release of fatty acids, which stimulate the secretion of fetuin-A by hepatocytes and adipocytes. Increased production of hepatokine A stimulates chemotaxis and penetration of macrophages into adipose tissue [8].…”

Section: Resultsmentioning

confidence: 99%

Pathogenetic role of fetuin-A in formation of metabolic disorders and systemic inflammation in patients with non-alcoholic fatty liver disease

Фадєєнко¹,

Kushnir²,

Chernova³

et al. 2022

СГ

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Non‑alcoholic fatty liver disease (NAFLD) remains the leading nosology among hepatic diseases around the world. Its complex pathogenesis is not still clearly understood. Besides metabolic changes one of potential mechanisms of NAFLD development is changes in hepatokines, fetuin‑A in particular, secretion and metabolism. Objective — to determine the role of fetuin‑A in the development and progression of NAFLD. Materials and methods. The study enrolled 78 NAFLD patients with metabolic disorders and 30 volunteers as a control group. Additionally to routine examination serum concentration of fetuin‑A was determined. Statistical processing was carried out using SPSS 21. Results. The results showed a statistically significant increase in fetuin‑A concentrations in NAFLD patients with concomitant MS (p < 0.05). There was a direct correlation between fetuin‑A levels and parameters of abdominal (WC and WHR, p < 0.05) and visceral obesity (VAT %, p < 0.05). Concentrations of fetuin‑A were higher in polymorbid patients, especially in the combination of NAFLD with type 2 diabetes mellitus and obesity. Fetuin‑A levels was associated with changes in carbohydrates and lipids parameters. Fetuin‑A positively correlated with glycated hemoglobin (r = 0.32, p < 0.05) and index HOMA (r = 0.36, p < 0.05). There was a positive correlation between fetuin‑A level and TG (r = 0.44, p < 0.05) and LDL cholesterol (r = 0.37, p < 0.05). Furthermore, an increase in fetuin‑A was associated with an increase in activity of ALT (r = 0.39, p < 0.05) and elevation of the level of TNF‑a (r = 0.33, p < 0.05). NAFLD patients with advanced stages of steatosis and fibrosis also demonstrated higher levels of fetuin‑A (p < 0.05). Conclusions. The obtained data indicate a significant pathogenetic role of fetuin‑A in the development and progression of NAFLD.

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“…Insulin resistance is defined as impaired signal transduction and biological actions in response to insulin stimulation, resulting in a decrease in the ability of insulin to increase glucose uptake and utilization [ 16 ]. Insulin resistance is a risk factor for non-alcoholic steatohepatitis, metabolic syndrome, and type 2 diabetes (T2D) [ 17 , 18 , 19 ]. MOTS-c has been demonstrated to increase insulin sensitivity in mice by preventing fat accumulation through reducing the pathways of sphingolipid metabolism, monoacylglycerol metabolism, and dicarboxylate metabolism [ 20 ].…”

Section: Mots-c Inhibits Pathological Metabolic Processesmentioning

confidence: 99%

MOTS-c Functionally Prevents Metabolic Disorders

Gao

Wei

et al. 2023

Metabolites

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Mitochondrial-derived peptides are a family of peptides encoded by short open reading frames in the mitochondrial genome, which have regulatory effects on mitochondrial functions, gene expression, and metabolic homeostasis of the body. As a new member of the mitochondrial-derived peptide family, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is regarding a peptide hormone that could reduce insulin resistance, prevent obesity, improve muscle function, promote bone metabolism, enhance immune regulation, and postpone aging. MOTS-c plays these physiological functions mainly through activating the AICAR-AMPK signaling pathways by disrupting the folate-methionine cycle in cells. Recent studies have shown that the above hormonal effect can be achieved through MOTS-c regulating the expression of genes such as GLUT4, STAT3, and IL-10. However, there is a lack of articles summarizing the genes and pathways involved in the physiological activity of MOTS-c. This article aims to summarize and interpret the interesting and updated findings of MOTS-c-associated genes and pathways involved in pathological metabolic processes. Finally, it is expected to develop novel diagnostic markers and treatment approaches with MOTS-c to prevent and treat metabolic disorders in the future.

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Fetuin-A in Activated Liver Macrophages Is a Key Feature of Non-Alcoholic Steatohepatitis

Cited by 14 publications

References 47 publications

Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations

Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations

Pathogenetic role of fetuin-A in formation of metabolic disorders and systemic inflammation in patients with non-alcoholic fatty liver disease

MOTS-c Functionally Prevents Metabolic Disorders

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