Biology subjects

Leclercq, I. A.

Publications and source records attributed to Leclercq, I. A..

4 recordsLinked to original sources

bioRxiv2025

Hepatic ADMA/PRMT1 axis regulation is associated with NO-dependent endothelial dysfunction in MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of fatty liver disease and a recognized cardiovascular risk factor, yet the mechanisms linking hepatic pathology to vascular dysfunction remain poorly understood. We aimed to investigate whether MASH impairs endothelial function via nitric oxide (NO)-dependent mechanisms and to identify potential liver-derived mediators involved in this process. Endothelial function was assessed in two murine MASH models, Foz mice fed a high-fat diet and C57BL/6JRj mice fed a western diet with fructose, by using wire myography, while blood pressure was monitored via telemetry. NO pathway was further investigated through eNOS expression and activation and Hb-NO measurements. ADMA metabolism was analyzed in both liver tissue and plasma by LC-MS and gene expressions. Additionally, bovine aortic endothelial cells (BAECs) were treated with mouse plasma to measure the circulating factors effects on eNOS activation and the role of oxidative stress. Both models exhibited impaired NO-dependent vasorelaxation without evidence of atherosclerosis. In Foz mice, this impairment was associated with reduced eNOS expression and activation. Surprisingly, plasma Hb-NO levels did not reflect vascular NO deficiency, likely due to elevated hepatic iNOS expression. In both models, hepatic and plasma ADMA levels were increased, concomitant with hepatic upregulation of Prmt1. BAECs exposed to plasma from MASH mice showed reduced eNOS activation independent of oxidative stress. Our findings reveal that MASH is consistently associated with NO-dependent endothelial dysfunction, with ADMA emerging as a key liver-derived mediator. The PRMT1/ADMA/NO axis may represent a mechanistic link between liver pathology and vascular impairment, positioning ADMA as a potential biomarker and therapeutic target for cardiovascular risk associated with MASH. HighlightsO_LIMASH is associated with impaired NO-dependent endothelial function in two distinct MASH models. C_LIO_LICirculating factors disrupt the NOS/NO pathway independently of oxidative stress C_LIO_LIReduced plasma Hb-NO levels do not accurately reflect NO-dependent endothelial dysfunction in a context of MASH. C_LIO_LIElevated plasma and hepatic ADMA levels associated with hepatic prmt1 upregulation are consistently observed in both MASH models. C_LIO_LIThe PRMT1/ADMA/NO axis emerges as a key liver-mediated mechanism driving endothelial dysfunction in MASH C_LI

physiology↗

bioRxiv2024

Liver Sinusoidal Endothelial Cells and Laminin dictate cholangiocytes fate in chronic liver disease

In chronic liver disease (CLD), hepatocyte senescence limits conventional regeneration, prompting an alternative regeneration mechanism through transdifferentiation of reactive cholangiocytes (or ductular reaction cells - DRs). Yet, this alone is insufficient to avoid liver failure and transplantation, highlighting the importance of a deeper understanding of the mechanism. We focused on the DRs microenvironment. We identified laminin as a crucial component of the extracellular matrix to maintain DRs in a biliary phenotype, preventing their differentiation into hepatocytes. Liver sinusoidal endothelial cells (LSEC) are the cells regulating laminin degradation around DRs. By preventing LSEC capillarization during CLD, we enhanced DR differentiation into hepatocytes. We also demonstrated this causality in human samples. This is the first time that a mechanism for DR-driven regeneration has been described.

cell biology↗

bioRxiv2022

The FXR agonist obeticholic acid does not stimulate liver regeneration in hepatectomized mice.

BackgroundPostresectional liver failure (PLF) is a dreaded complication after partial hepatectomy (PH). Data from animal experiments indicate that endogenous ligands (i.e. bile salts) can stimulate liver regeneration and prevent liver injury after PH, via hepatic Fxr and the ileal Fxr-Fgf15 axis. AimTo investigate whether exogenous activation of the Fxr pathway with the semi-synthetic bile acid derivative obeticholic acid (OCA) could stimulate postresectional liver regeneration in mice. MethodsTwelve weeks old male C57BL6/J mice were pre-treated with OCA (10 mg/kg/day) or vehicle, and after 7 days subjected to 70% PH. Mice were sacrificed at 24, 48 and 72 hrs after PH, and liver injury, secretory function, and regenerative indices were assessed. In a second study, OCA pre-treated mice received oral sucrose supplementation in the postoperative trajectory, and a group of mice receiving intraperitoneal injection of FGF19 was included as a positive control group. Here, mice were sacrificed at 48 hours after PH. ResultsNo effect could be detected on liver mass recovery after PH, although responses of Cyp7a1, Cyp8b1 and other Fxr target genes implied general effectiveness of OCA treatment. OCA had no consistent effects on the number of Ki-67+ hepatocytes and mitotic figures around the peak of proliferation (i.e. 48 hrs) after PH, having no effect or increasing these regenerative indices in the consecutive experiments. Hepatic bile salt content, an important determinant of PH-induced liver regeneration, at this time point was not affected by OCA. After pretreatment of mice with FGF19, a reduced expression of ileal bile salt-regulated genes Fgf15 and Slc51b indicating FGF19-mediated repression of bile salt synthesis was seen, but this did not stimulate postresectional liver regeneration in mice. ConclusionDespite the activation of hepatic and ileal Fxr as shown by induction of target genes, treatment with OCA or FGF19 did not result in accelerated liver regeneration after PH and liver bile salt content was not influenced. We speculate that bile salt homeostasis and endogenous bile salt signaling is already optimal in unaffected livers for proper progression of regeneration after PH. It will be interesting to study the effects of Fxr agonism on liver regeneration after PH, and prevention of PLF in the context of compromised bile salt homeostasis/signaling prior to PH.

cell biology↗

bioRxiv2022

Development of a mouse model for postresectional liver failure.

BackgroundPostresectional liver failure (PLF) is a dreaded complication after extended liver resection. Post-operative hyperbilirubinemia suggests that impaired hepatobiliary transport with intrahepatic accumulation of harmful cholephiles plays an etiological role. Bile salts serve dual roles as signaling molecules engaged in liver regeneration after partial hepatectomy (PH) and biological detergents. AimIn this study we tested the hypothesis that excessive accumulation of bile salts in the regenerating liver results in PLF. MethodsTwelve weeks old male C57BL6/J mice were subjected to 70% PH and post-operatively challenged with a diet supplemented with cholic acid (CA, 0.5 or 1.0%; n=5-6 per group) or a control diet. After 48 hours mice were sacrificed, and liver injury, secretory function, and regenerative indices were assessed. ResultsMice fed a 1.0% CA diet displayed more pronounced weight loss following PH and had a deranged post-operative glucose course. Liver injury (aminotransferase elevations) and impaired hepatobiliary transport function (hyperbilirubinemia) were apparent in the group fed a 1.0% CA diet, but not in animals fed a 0.5% CA diet. No differences in liver mass recovery were observed among groups. However, the percentage of hepatocytes staining positive for the proliferation marker Ki-67 were reduced in mice receiving a 1.0% CA diet relative to animals fed a 0.5% CA diet. PH-induced expression of key factors involved in cell cycle progression (e.g. Foxm1b, Cdc25b) was abrogated in the 1.0% CA group. ConclusionA postresectional challenge with a 1.0% CA diet induces signs of liver injury and defective liver regeneration. A longer duration of the dietary challenge and/or secondary hits may further improve the model. Once validated, it can be used to evaluate pharmaceutical strategies to prevent or treat PLF.

cell biology↗