Biology subjects

Bertrand-Michel, J.

Publications and source records attributed to Bertrand-Michel, J..

11 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↗

bioRxiv2025

Human bone marrow adipocytes drive prostate cancer bone metastasis progression via lipid-mediated induction of Angiopoietin-like 4

Bone is the main metastatic site in advanced prostate cancer (PCa) and contains bone marrow adipocytes (BMAds), which account for more than 70% of adult bone marrow. However, their role in the progression of PCa metastases remains poorly understood. Herein, we developed a physiologically relevant 3D culture model using primary human BMAds from red hematopoietic rich-areas (rBMAds) and we showed that rBMAds engage in metabolic crosstalk with PCa cells. Specifically, rBMAds release free fatty acids (FFAs) through a non-canonical lipolytic pathway and these FFAs are taken up by PCa cells inducing a transcriptional reprogramming that promotes motility. Among the responsive genes, Angiopoietin like 4 (ANGPTL4) is the most upregulated via a peroxisome proliferator-activated receptor {gamma}-dependent mechanism, and its silencing abolishes the rBMAd-driven migratory and invasive phenotype. Clinically, elevated ANGPTL4 expression is associated with poor overall survival specifically in PCa bone metastases, is maintained during metastatic progression, and is indicative of aggressive disease. Together, our findings uncover a novel adipocyte-tumor interaction and identify ANGPTL4 as a key mediator and potential therapeutic target in bone-metastatic PCa.

cancer biology↗

bioRxiv2025

Red bone marrow hosts metabolically active anucleate adipocytes that support hematopoiesis

Bone marrow adipocytes (BMAds) are a major component of the bone marrow (BM) that regulate bone turnover and hematopoiesis. In rodents, two distinct adipocyte populations exist: constitutive BMAds (cBMAds), located in areas devoid of hematopoietic cells and resistant to metabolic cues, and regulatory BMAds (rBMAds), interspersed within hematopoietic niches and responsive to energy stress. Despite their potential importance, rBMAds have remained poorly characterized due to their scarcity in rodents. Here, we used a high-yield method to isolate human rBMAds, enabling structural, proteomic, lipidomic, and functional analyses. Remarkably, human rBMAds are anucleate yet retain organelles and maintain lipid and glucose metabolism, but unlike their rodent counterparts, they lack lipolytic activity. They actively secrete factors that support hematopoiesis in vitro, implicating them as functional contributors to the BM niche. These findings suggest that human rBMAds may arise from cBMAds through terminal differentiation and define a novel adipocyte subtype critical for BM homeostasis.

cell biology↗

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

Effect of thermoneutral housing on MASLD severity, hepatic gene expression, and BAT activation during beta3-adrenergic stimulation in mice

Metabolic dysfunction-associated steatotic liver disease (MASLD), and its more advanced stage metabolic dysfunction-associated steatohepatitis, is the most common chronic liver disease, constituting a major public health issue. No medication is approved for MASLD treatment, and relevant preclinical models are needed to define molecular mechanisms underlying MASLD pathogenesis, and evaluate therapeutic approaches. Here we demonstrated that compared to standard temperature housing, thermoneutral housing aggravated western diet (WD)-induced obesity, diabetes, and steatosis in male mice, which was associated with increased hepatic expression of inflammation- and fibrosis-related genes. Accordingly, compared to standard-housed mice, thermoneutral-housed WD-fed mice developed more severe hepatic inflammation and fibrosis. The liver is the central metabolic organ in whole-body metabolic homeostasis. We used thermoneutrally housed mice with WD-induced MASLD to examine the effect of MASLD during {beta}3- adrenergic stimulation, and found that diet-induced MASLD was associated with defective inter- organ metabolic cross-talk, leading to impaired brown adipose tissue activation. HighlightsO_LIThermoneutral housing promotes WD-induced obesity and MASLD in mice C_LIO_LIThermoneutral housing fosters WD-induced change in gene expression C_LIO_LIThermoneutral housing fosters hepatic inflammation and fibrosis C_LIO_LIMASLD is associated with defective BAT response to {beta}3-adrenergic stimulation C_LI

physiology↗

bioRxiv2024

p110α-dependent hepatocyte signaling is critical for liver gene expression and its rewiring in MASLD

Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is dependent on PI3K. We used mice lacking p110, the catalytic subunit of PI3K, to investigate its role in the regulation of liver gene expression in health and in Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). The absence of hepatocyte PI3K signaling promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3K signaling. In addition, though PI3K deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3K, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110 in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.

cell biology↗

bioRxiv2023

PIEZO1 force sensing controls global lipid homeostasis

How cardiovascular activity beneficially regulates lipid homeostasis is unclear. Here we hypothesise a mechanism in which mechanical force sensed by PIEZO1 ion channels in endothelium links blood flow to lipid regulation. We engineered mice for conditional deletion of PIEZO1 in endothelium and determined consequences for lipid regulation. Prominent are upregulated expression of hepatic Cyp7a1 and intestinal Ldlr genes, which are pivotal in cholesterol catabolism and excretion. Consistent with such regulation is endothelial PIEZO1-dependence of hepatic, intestinal and whole body cholesterol and bile homeostasis. There is organ perfusion-dependent gene regulation via endothelial PIEZO1 and downstream nitric oxide synthase. Endothelial PIEZO1-deleted mice are protected against hyperlipidaemia and ectopic fat deposition. Human PIEZO1 gene variants and a recapitulated human PIEZO1 gain-of-function variant in mice associate with dyslipidaemia. The data suggest lipid-promoting effects of endothelial force sensing and new opportunity for understanding and addressing problems of hyperlipidaemia.

physiology↗

bioRxiv2022

Obesity promotes Fumonisin B1 toxicity and induces hepatitis

Background and aimObesity is a major public health issue worldwide. Obesity is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. This toxin provokes severe mycotoxicosis in animals, which leads to hepatotoxicity and alterations in the immune response and intestinal barrier permeability. We investigated here whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. MethodsThe metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the last three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water. ResultsAs expected, HFD feeding induced significant body weight gain, glucose intolerance, and hepatic steatosis. FB1-exposed mice displayed a higher sphinganine/sphingosine ratio, a well-known FB1 biomarker of exposure, due to inhibition of ceramide synthases activity by FB1. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. ConclusionThese results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.

pharmacology and toxicology↗

bioRxiv2021

De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtbs capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However, upon activation macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of key immunomodulatory eicosanoids. Here, we asked whether de novo synthesis of PUFAs is modulated in Mtb-infected macrophages and benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection activates the early PUFA biosynthetic pathway for production of eicosanoids. While PUFA synthesis blockade significantly impaired the inflammatory and antimicrobial responses of infected macrophages, it had no effect on Mtb growth in vivo. Using a click-chemistry approach, we found that Mtb efficiently imports PUFAs of the {omega}6 subset via Mce1 in axenic culture, including the eicosanoid precursor arachidonic acid (AA). Notably, Mtb preferentially internalized AA over all other FAs within infected macrophages, but here Mtbs import of AA was largely Mce1-independent and correlated with elevated AA uptake by host cells. Together, these findings reveal AA as a major FA substrate for intracellular Mtb. They suggest that Mtbs hijacking of host-derived AA may counteract its stimulatory effect on anti-mycobacterial immune responses.

immunology↗

bioRxiv2020

Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3K activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3K-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3K inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3K inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour-cell intrinsic PI3K therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution. The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood. RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3K activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3K is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3K activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3K is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K -selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3K activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3K delayed primary tumour and micro-metastasis evolution. Finally, PI3K activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution. IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3K-selective inhibitors significantly delay metastatic progression and death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/307884v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a5a8b4org.highwire.dtl.DTLVardef@1e6e18dorg.highwire.dtl.DTLVardef@e22859org.highwire.dtl.DTLVardef@1c7148b_HPS_FORMAT_FIGEXP M_FIG Pancreatic ductal adenocarcinoma requires tumour-intrinsic PI3K activity to accelerate inflammatory metastatic disease. Biorender illustration. C_FIG

cancer biology↗

bioRxiv2018

Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity

ObjectivesPeroxisome proliferator activated receptor (PPAR) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Ppar in hepatocytes spontaneously develop steatosis without obesity in aging. Altough steatosis is a benign condition it can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. Several drugs are being tested in clinical trials, including pharmacological agonists for the different PPAR isotypes. In current study, we investigated the role of hepatocyte PPAR in a preclinical model of steatosis.\n\nMethods/ResultsWe have investigated the role of hepatocyte PPAR in a preclinical model of steatosis using High Fat Diet (HFD) feeding as a model of obesity in C57BL/6J male Wild-Type mice (WT), in whole-body (Ppar-/-) mice and in mice lacking Ppar in hepatocyte (Pparhep-/-). We provide evidence that Ppar deletion in hepatocytes promotes NASH in mice fed an HFD. This enhanced NASH susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPAR activity predominantly contributes to the metabolic response to HFD.\n\nConclusionTaken together, our data support hepatocyte PPAR as being essential to the prevention of steatosis progression to NASH and that extra-hepatocyte PPAR activity contributes to whole-body lipid homeostasis.\n\nHighlightsO_LIPpar deletion in hepatocytes promotes steatosis and inflammation in HFD-induced obesity\nC_LIO_LIHepatocyte-specific deletion of Ppar dissociates NAFLD from glucose intolerance in HFD-induced obesity obesity\nC_LIO_LIExtrahepatic PPAR activity contributes to the metabolic response to HFD-induced obesity\nC_LI

pathology↗