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Hepatic FNDC5 is a potential local protective factor against Non-Alcoholic Fatty Liver.
- Source :
-
Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2020 May 01; Vol. 1866 (5), pp. 165705. Date of Electronic Publication: 2020 Jan 27. - Publication Year :
- 2020
-
Abstract
- The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK, a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5-silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N-acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death.<br />Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Adult
Apoptosis
Bariatric Surgery
Biopsy
Diet, High-Fat adverse effects
Female
Fibronectins blood
Fibronectins genetics
Gene Expression Profiling
Hep G2 Cells
Hepatocytes metabolism
Humans
Insulin Resistance
Lipogenesis
Liver cytology
Male
Middle Aged
Non-alcoholic Fatty Liver Disease blood
Non-alcoholic Fatty Liver Disease etiology
Obesity, Morbid blood
Obesity, Morbid pathology
Obesity, Morbid surgery
Phosphoenolpyruvate Carboxykinase (ATP) metabolism
Primary Cell Culture
Protective Factors
Up-Regulation
Fibronectins metabolism
Liver pathology
Non-alcoholic Fatty Liver Disease pathology
Obesity, Morbid complications
Subjects
Details
- Language :
- English
- ISSN :
- 1879-260X
- Volume :
- 1866
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta. Molecular basis of disease
- Publication Type :
- Academic Journal
- Accession number :
- 32001301
- Full Text :
- https://doi.org/10.1016/j.bbadis.2020.165705