Biology subjects

Martin, C. M. P.

Publications and source records attributed to Martin, C. M. P..

5 recordsLinked to original sources

bioRxiv2026

The constitutive androstane receptor protects against metabolic dysfunction-associated steatotic liver disease through sex specific interactions with the gut microbiota

Background: The gut-liver axis is involved in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), but the host molecular actors involved in such dialogue have not yet been fully characterized. Objective: We investigated the sex-dependent role of the Constitutive Androstane Receptor (CAR) as a hepatic sensor of microbial signals in MASLD pathophysiology. Design: Male and female Car+/+ and Car-/- mice were fed a western diet (WD) for 4, 14 or 35 weeks. We performed plasma biochemistry, liver histology, bile acid and cholesterol quantification, untargeted multi-omics approach combining liver RNA-sequencing and 16S rRNA sequencing, together with co-housing, fecal microbiota transplantation and analysis of publicly available transcriptomics data in human cohorts. Results: Short-term WD revealed CAR-dependent protection against steatosis, together with perturbations in the transcriptional signatures of multiple transcription factors involved in hepatocyte identity in males. After 14 weeks, CAR deletion increased WD-induced liver damage, inflammation and fibrosis, and disrupted bile acid, cholesterol and gut microbiota homeostasis, in males only. Co-housing and fecal microbiota transplantations revealed that a Car+/+ gut microbiota protected against WD-induced liver damage, while a Car-/- microbiota was reshaped by a Car+/+ host. No CAR-dependent phenotype was observed in females. Finally, in human cohorts, hepatic CAR expression decreased in advanced clinical stages of MASLD. Conclusion: CAR is a sex-dependent protective nuclear receptor against MASLD progression, acting both as a transcriptional regulator of hepatocyte identity and as a mediator of the host-microbiota crosstalk.

physiology↗

bioRxiv2026

Diet modulates metabolic and hepatic responses to chronic pesticide mixture exposure in mice

Chronic exposure to pesticide mixtures through diet is common, yet their combined metabolic effects and interactions with dietary factors remain unclear. We identified four pesticides prevalent in human exposure (imazalil, thiabendazole, boscalid, lambda-cyhalothrin) and assessed their combined impacts on hepatic metabolism and metabolic homeostasis using human liver cells and male mice fed standard chow or western diets. We found that the pesticide mixture induced metabolic perturbations in human hepatocytes. In addition, the pesticide mixture altered hepatic gene expression in chow-fed mice and exacerbated western diet-induced glucose intolerance, fasting hyperglycemia, and insulin resistance without affecting body weight or liver steatosis. These findings reveal that dietary context influences the metabolic consequences of pesticide mixtures, highlighting the need to consider nutritional status when evaluating environmental contaminant risks. Our results suggest that pesticide mixtures at reference doses may contribute to metabolic dysregulation, particularly under obesogenic dietary conditions. Highlights- Four common pesticides in mixture disrupt metabolism in liver cells - Dietary exposure to this pesticide mixture alters hepatic gene expression in mice - The pesticide mixture exacerbates WD-induced disruptions in glucose homeostasis - Pesticides and diet interact in producing the metabolic effects of a pesticide mixture

pharmacology and toxicology↗

bioRxiv2025

Soluble and insoluble dietary fibres differentially affect liver steatosis and gut microbiota in western-diet fed mice

ScopeMetabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic hepatic liver disease. An imbalance diet, rich in lipids and sugars and low in fibre, is a key contributing factor. However, there is limited knowledge about how soluble and fermentable dietary fibres, compared to insoluble and non-fermentable fibres, differently affect liver metabolism through their interactions with the intestinal microbiota. Methods and resultsMale mice housed at thermoneutrality were fed a Western Diet (WD) supplemented with fermentable inulin or non-fermentable cellulose for 18 weeks. Inulin supplementation mitigated WD-induced obesity, glucose intolerance, dyslipidemia and protected against WD-induced hepatic steatosis compared to cellulose. Hepatic gene expression changes induced by WD were attenuated with inulin. Additionally, inulin preserved gut microbiota composition and metabolism, indicating greater resilience against diet-induced perturbations. ConclusionThese findings suggest that soluble dietary fibres like inulin confer superior metabolic and hepatic benefits over insoluble fibres by modulating the gut microbiota-liver axis, highlighting their potential role in MASLD management.

physiology↗

bioRxiv2024

Testing the contribution of fibrinogen like 1 to the pathogenesis of metabolic dysfunction associated steatotic liver disease and hepatocellular carcinoma

Metabolic dysfunction-associated steatotic liver disease (MASLD) begins with simple steatosis, which can progress to hepatocellular carcinoma (HCC). The pathogenesis of MASLD alters the secretion of hepatokines such as fibrinogen-like 1 (FGL1), a candidate mediator of liver steatosis and hyperglycemia. To investigate the contribution of FGL1 to liver diseases, we compared wild-type mice to mice with hepatocyte-specific deletion of Fgl1 subjected to a steatosis or HCC experimental protocol. We found that mice deficient for Fgl1 in hepatocytes showed higher levels of plasma glucose, pronounced metabolic alterations and liver injury when fed a western diet compared to their wild-type counterparts. However, both genotypes exhibited a similar lipid deposition in the liver. Similarly, wild type and Fgl1-deficient mice displayed comparable liver alterations during HCC progression. We observed that FGL1 expression was repressed during MASLD progression in mice and human concomitantly with the severity of liver injury. Altogether, these findings suggest that FGL1 is not a major contributor to the pathogenesis of MASLD and HCC.

pathology↗

bioRxiv2023

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism

Background and AimsThe constitutive androstane receptor (CAR) is a nuclear receptor able to recognize a large panel of xenobiotics leading to the modulation of the expression of its target genes involved in xenobiotic detoxication and energy metabolism. While CAR hepatic activity is thought to be higher in women than in men, its response to an acute pharmacological activation has never been investigated in both sexes. MethodsHepatic transcriptome, plasma and hepatic metabolome, have been analyzed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), or with vehicle. ResultsWhile 90% of TCPOBOP-sensitive genes were modulated in a sex- independent way, the remaining 10% were almost exclusively impacted in female liver specifically. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation and extracellular matrix organization. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Data mining on human data confirmed that CAR activation may be involved in sexually-dimorphic drug-induced liver injury. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and associated with a decrease of hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a possible role in the control of TMAO homeostasis, CAR activation decreased platelet hyperresponsiveness in female mice supplemented with dietary choline. ConclusionsOur results demonstrate that more than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic response such as platelet aggregation. Also, CAR activation may be an important mechanism of sexually- dimorphic drug-induced liver injury.

pharmacology and toxicology↗