Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis

Fondevila, Marcos F.; Fernandez, Uxia; Heras, Violeta; Parracho, Tamara; Gonzalez-Rellan, María J.; Novoa, Eva María; Porteiro, Begoña; Alonso, Cristina; Mayo, Rebeca; Lima, Natália da Silva; Iglesias, Cristina; Filliol, Aveline; Senra, Ana; Delgado, Teresa C.; Woodhoo, Ashwin; Herrero, Laura; Serra, Dolors; Prévot, Vincent; Schwaninger, Markus; López, Miguel; Diéguez, Carlos; Millet, Óscar; Mato, José M.; Cubero, Francisco Javier; Varela‐Rey, Marta; Iruzubieta, Paula; Crespo, Javier; Martínez‐Chantar, María Luz; Schwabe, Robert F.; Nogueiras, Rubén

doi:10.1016/j.jhep.2022.02.003

Cited by 50 publications

(23 citation statements)

References 40 publications

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“…This finding could also associate C. difficile -derived MVs with the development of NAFLD and NASH. Recently, it has been reported that CPT1A was overexpressed in hepatic stellate cells from patients with liver fibrosis, correlating positively with fibrosis and NAFLD activity score [ 58 ]. Furthermore, the specific deletion of CPT1A in mouse hepatic stellate cells protected against fibrosis [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been reported that CPT1A was overexpressed in hepatic stellate cells from patients with liver fibrosis, correlating positively with fibrosis and NAFLD activity score [ 58 ]. Furthermore, the specific deletion of CPT1A in mouse hepatic stellate cells protected against fibrosis [ 58 ]. On the other hand, the liver of an animal model with deficient CPT1A function likely represents a “healthy” fatty liver that fights against the deleterious actions of the high-fat diet on hepatic injury [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

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Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells

et al. 2023

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Clostridioides difficile infection (CDI) appears to be associated with different liver diseases. C. difficile secretes membrane vesicles (MVs), which may be involved in the development of nonalcoholic fatty liver disease (NALFD) and drug-induced liver injury (DILI). In this study, we investigated the presence of C. difficile-derived MVs in patients with and without CDI, and analyzed their effects on pathways related to NAFLD and DILI in HepG2 cells. Fecal extracellular vesicles from CDI patients showed an increase of Clostridioides MVs. C. difficile-derived MVs that were internalized by HepG2 cells. Toxigenic C. difficile-derived MVs decreased mitochondrial membrane potential and increased intracellular ROS compared to non-toxigenic C. difficile-derived MVs. In addition, toxigenic C. difficile-derived MVs upregulated the expression of genes related to mitochondrial fission (FIS1 and DRP1), antioxidant status (GPX1), apoptosis (CASP3), glycolysis (HK2, PDK1, LDHA and PKM2) and β-oxidation (CPT1A), as well as anti- and pro-inflammatory genes (IL-6 and IL-10). However, non-toxigenic C. difficile-derived MVs did not produce changes in the expression of these genes, except for CPT1A, which was also increased. In conclusion, the metabolic and mitochondrial changes produced by MVs obtained from toxigenic C. difficile present in CDI feces are common pathophysiological features observed in the NAFLD spectrum and DILI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells

et al. 2023

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“…The human hepatic stellate cell line LX‐2 was purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). LX‐2 cells were maintained in DMEM/GlutaMAX I medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (Fondevila et al, 2022). When LX‐2 cells were at approximately 60% confluence, they were starved in FBS‐free DMEM/GlutaMAX I medium for 24 h prior to treatment with 2 ng·mL −1 TGFβ1 (HY‐P7118, MedChemExpress, Shanghai, China) and SCL.…”

Section: Methodsmentioning

confidence: 99%

Sclareol attenuates liver fibrosis through SENP1‐mediated VEGFR2 SUMOylation and inhibition of downstream STAT3 signaling

Niu

Bao

et al. 2023

Phytotherapy Research

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Liver fibrosis is a key global health care burden. Sclareol, isolated from Salvia sclarea, possesses various biological activities. Its effect on liver fibrosis remains unknown. This study was proposed to evaluate the antifibrotic activity of sclareol (SCL) and explore its underlying mechanisms. Stimulated hepatic stellate cells served as an in vitro liver fibrosis model. The expression of fibrotic markers was assessed by western blot and real‐time PCR. Two classical animal models, bile duct‐ligated rats and carbon tetrachloride‐treated mice, were utilized for the in vivo experiments. The liver function and fibrosis degree were determined by serum biochemical and histopathological analyses. VEGFR2 SUMOylation was analyzed using coimmunoprecipitation assay. Our results indicated that SCL treatment restricted the profibrotic propensity of activated HSCs. In fibrotic rodents, SCL administration alleviated hepatic injury and reduced collagen accumulation. Mechanistic studies indicated that SCL downregulated the protein level of SENP1 and enhanced VEGFR2 SUMOylation in LX‐2 cells, which affected its intracellular trafficking. Blockade of the interaction between VEGFR2 and STAT3 was observed, resulting in the suppression of downstream STAT3 phosphorylation. Our findings demonstrated that SCL has therapeutic efficacy against liver fibrosis through mediating VEGFR2 SUMOylation, suggesting that SCL may be a potential candidate compound for its treatment.

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“…Activation of the gut FXR/FGF19 signaling pathway inhibits the key lipogenic enzyme, acetyl-CoA carboxylase, supporting the downregulation of de novo fatty acid production by hepatic FXR Frontiers in Pharmacology frontiersin.org and indirectly promoting fatty acid oxidation by downregulating the expression of carnitine palmitoyl transferase 1α (CPT1α) serving as a key mitochondrial fatty acid transporter. Recent studies have shown that CPT1α is elevated in HSCs from fibrotic patients and mouse models of fibrosis, and that CPT1α induces activation of these cells leading to fibrosis (Fondevila et al, 2022).…”

Section: Changes In Bile Acid Metabolism Transport and Signal Transdu...mentioning

confidence: 99%

Bariatric surgery for diabetic comorbidities: A focus on hepatic, cardiac and renal fibrosis

Ding

Zhang

et al. 2022

Front. Pharmacol.

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Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis

Cited by 50 publications

References 40 publications

Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells

Membrane Vesicles of Toxigenic Clostridioides difficile Affect the Metabolism of Liver HepG2 Cells

Sclareol attenuates liver fibrosis through SENP1‐mediated VEGFR2 SUMOylation and inhibition of downstream STAT3 signaling

Bariatric surgery for diabetic comorbidities: A focus on hepatic, cardiac and renal fibrosis

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