Impaired LXRa phosphorylation attenuates progression of fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target

Nuclear Receptors and Clock Components in Cardiovascular Diseases

Cardiovascular diseases (CVD) are still the first cause of death worldwide. Their main origin is the development of atherosclerotic plaque, which consists in the accumulation of lipids and inflammatory leucocytes within the vascular wall of large vessels. Beyond dyslipidemia, diabetes, obesity, hypertension and smoking, the alteration of circadian rhythms, in shift workers for instance, has recently been recognized as an additional risk factor. Accordingly, targeting a pro-atherogenic pathway at the right time window, namely chronotherapy, has proven its efficiency in reducing plaque progression without affecting healthy tissues in mice, thus providing the rationale of such an approach to treat CVD and to reduce drug side effects. Nuclear receptors are transcriptional factors involved in the control of many physiological processes. Among them, Rev-erbs and RORs control metabolic homeostasis, inflammatory processes and the biological clock. In this review, we discuss the opportunity to dampen atherosclerosis progression by targeting such ligand-activated core clock components in a (chrono-)therapeutic approach in order to treat CVD

Mécanismes moléculaires de la régulation du récepteur nucléaire humain PPAR alpha (un rôle clef des modifications post-traductionnelles)

Le récepteur nucléaire PPARa joue un rôle majeur dans la régulation du métabolisme des lipides et dans le contrôle de la réponse inflammatoire au travers de mécanismes génomiques de cis-activation et non-génomiques de trans-répression, respectivement. L'activité cis-activatrice de PPARa peut être augmentée par le recrutement de coactivateurs (SRC-1 et CBP) et inhibée par les corépresseurs (NCoR et SMRT). Cette activité peut dépendre de la présence de ligand (acides gras, fibrates). En plus de la liaison du ligand, l'activité de PPARa est régulée par des modifications post-traductionnelles telles que la phosphorylation et l'ubiquitination. Cependant, les mécanismes moléculaires liés à la régulation de l'activité de PPARa restent cependant peu connus. Nous nous sommes plus particulièrement intéressés à la SUMOylation et nous avons montré que l'activité de PPARa peut être régulée par cette modification post-traductionnelle. De manière très intéressante, nous avons montré que le site de SUMOylation de PPARa est très proche des sites de phosphorylation par les Protéines Kinases C (PKC) du récepteur. Nous nous sommes donc intéressés aux rôles de la phosphorylation de PPARa humain par les PKC sur la régulation de l'activité et de la SUMOylation du récepteur. Dans un premier temps, nous avons montré que la protéine hPPARa est SUMOylée par SUMO-1 (Small Ubiquitin-like MOdifier-1) sur la lysine 185 de son domaine charnière. L'inhibition spécifique de la SUMOylation sur ce site augmente l'activité cis-activatrice de PPARa en inhibant le recrutement du corépresseur NCoR mais pas celui de SMRT. Enfin, la SUMOylation de hPPARa est régulée par la présence de ligand spécifique, par la SUMO E3 ligase PIASy. De plus, il a été montré au laboratoire que les PKC-a et -bII phosphorylent le son domaine charnière de hPPARa au niveau des sérines 179 et 230. Cependant, les mécanismes moléculaires liés à la régulation de hPPARa par les PKC restaient inconnus. Ainsi, nous avons montré que la phosphorylation des sérines 179 et 230 inhibe l'activité cis-activatrice de hPPARa en favorisant le recrutement du corépresseur SMRT mais pas de NCoR. Nous avons également montré que la phosphorylation par les PKC diminue la SUMOylation de PPARa, suggérant une interconnexion entre ces deux modifications post-traductionnelles. En conclusion, la phosphorylation et la SUMOylation de hPPARa au niveau de sa région charnière agiraient comme un interrupteur moléculaire régulant spécifiquement l'activité transcriptionnelle de hPPARa au travers du recrutement spécifique de ses cofacteursLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Récepteurs nucléaires et rythmes circadiens : Implications dans les maladies inflammatoires

International audienceThe biological clock is a set of evolutionarily conserved "clock proteins" that generate circadian rhythms in behavior and physiological processes. The clock programs these processes at specific times of the day, allowing the organism to optimize its functions by anticipating predictable daily changes such as day/night, hence sleep/wake or feeding/fasting cycles. Modern lifestyle, i.e., exposure to light at night, shift work and irregular eating patterns and sleep schedules desynchronize the clocks residing in each organ. This dissonance is associated with an increased risk of developing various diseases such as cancer, metabolic, cardiovascular and chronic inflammatory diseases.L’horloge circadienne programme l’ensemble des processus physiologiques, dont l’activité du système immunitaire, à des moments précis de la journée. Elle permet d’optimiser les fonctions de l’organisme en anticipant les changements quotidiens tels que les cycles jour/nuit. Nos habitudes de vie comme l’exposition à la lumière artificielle ou une prise alimentaire irrégulière désynchronisent cependant cette horloge et provoquent des maladies, par exemple inflammatoires. Au niveau moléculaire, elle consiste en un réseau de facteurs de transcription dont certains sont des récepteurs nucléaires, activables par des ligands. Une meilleure compréhension des rythmes biologiques et du rôle des récepteurs nucléaires de l’horloge circadienne permettrait d’ouvrir un champ thérapeutique nouveau. La chronothérapie qui consiste en l’administration d’un composé pharmacologique au moment de la journée le plus propice, permettrait, en ciblant ces récepteurs, d’optimiser l’efficacité du traitement et d’en réduire les possibles effets secondaires

Acetate Improves the Killing of Streptococcus pneumoniae by Alveolar Macrophages via NLRP3 Inflammasome and Glycolysis-HIF-1α Axis

International audienceShort-chain fatty acids (SCFAs) are metabolites produced mainly by the gut microbiota with a known role in immune regulation. Acetate, the major SCFA, is described to disseminate to distal organs such as lungs where it can arm sentinel cells, including alveolar macrophages, to fight against bacterial intruders. In the current study, we explored mechanisms through which acetate boosts macrophages to enhance their bactericidal activity. RNA sequencing analyses show that acetate triggers a transcriptomic program in macrophages evoking changes in metabolic process and immune effector outputs, including nitric oxide (NO) production. In addition, acetate enhances the killing activity of macrophages towards Streptococcus pneumoniae in an NO-dependent manner. Mechanistically, acetate improves IL-1β production by bacteria-conditioned macrophages and the latter acts in an autocrine manner to promote NO production. Strikingly, acetate-triggered IL-1β production was neither dependent of its cell surface receptor free-fatty acid receptor 2, nor of the enzymes responsible for its metabolism, namely acetyl-CoA synthetases 1 and 2. We found that IL-1β production by acetate relies on NLRP3 inflammasome and activation of HIF-1α, the latter being triggered by enhanced glycolysis. In conclusion, we unravel a new mechanism through which acetate reinforces the bactericidal activity of alveolar macrophages

SUMOylation of Human Peroxisome Proliferator-activated Receptor α Inhibits Its Trans-activity through the Recruitment of the Nuclear Corepressor NCoR*

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a key regulator of genes implicated in lipid homeostasis and inflammation. PPARα trans-activity is enhanced by recruitment of coactivators such as SRC1 and CBP/p300 and is inhibited by binding of corepressors such as NCoR and SMRT. In addition to ligand binding, PPARα activity is regulated by post-translational modifications such as phosphorylation and ubiquitination. In this report, we demonstrate that hPPARα is SUMOylated by SUMO-1 on lysine 185 in the hinge region. The E2-conjugating enzyme Ubc9 and the SUMO E3- ligase PIASy are implicated in this process. In addition, ligand treatment decreases the SUMOylation rate of hPPARα. Finally, our results demonstrate that SUMO-1 modification of hPPARα down-regulates its trans-activity through the specific recruitment of corepressor NCoR but not SMRT leading to the differential expression of a subset of PPARα target genes. In conclusion, hPPARα SUMOylation on lysine 185 down-regulates its trans-activity through the selective recruitment of NCoR

The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms

IL-18 is a member of the IL-1 family involved in innate immunity and inflammation. Deregulated levels of IL-18 are involved in the pathogenesis of multiple disorders including inflammatory and metabolic diseases, yet relatively little is known regarding its regulation. Liver X receptors or LXRs are key modulators of macrophage cholesterol homeostasis and immune responses. Here we show that LXR ligands negatively regulate LPS-induced mRNA and protein expression of IL-18 in bone marrow-derived macrophages. Consistent with this being an LXR-mediated process, inhibition is abolished in the presence of a specific LXR antagonist and in LXR-deficient macrophages. Additionally, IL-18 processing of its precursor inactive form to its bioactive state is inhibited by LXR through negative regulation of both pro-caspase 1 expression and activation. Finally, LXR ligands further modulate IL-18 levels by inducing the expression of IL-18BP, a potent endogenous inhibitor of IL-18. This regulation occurs via the transcription factor IRF8, thus identifying IL-18BP as a novel LXR and IRF8 target gene. In conclusion, LXR activation inhibits IL-18 production through regulation of its transcription and maturation into an active pro-inflammatory cytokine. This novel regulation of IL-18 by LXR could be applied to modulate the severity of IL-18 driven metabolic and inflammatory disorders