CIG – NEWS

Nat Commun. 2021 May 5;12(1):2538. doi: 10.1038/s41467-021-22764-2.

PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions

Giuseppe Ercolano ^1 2, Alejandra Gomez-Cadena ^1 2, Nina Dumauthioz ³, Giulia Vanoni ³, Mario Kreutzfeldt ⁴, Tania Wyss ³, Liliane Michalik ⁵, Romain Loyon ^6 7, Angela Ianaro ⁸, Ping-Chih Ho ³, Christophe Borg ^6 7, Manfred Kopf ⁹, Doron Merkler ⁴, Philippe Krebs ¹⁰, Pedro Romero ³, Sara Trabanelli ^1 2, Camilla Jandus ^11 12Affiliations expand

• PMID: 33953160
• DOI: 10.1038/s41467-021-22764-2

Free article

Abstract

Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.

Cancers (Basel). 2021 Apr 29;13(9):2153. doi: 10.3390/cancers13092153.

PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis

Hong Sheng Cheng ¹, Yun Sheng Yip ¹, Eldeen Kai Yi Lim ², Walter Wahli ^1 3 4, Nguan Soon Tan ^1 2Affiliations expand

Free article

Abstract

Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.

Keywords: cancer-associated adipocyte; cancer-associated fibroblast; metabolic reprogramming; peroxisome proliferation-activated receptor; tumor-associated macrophage.

• PMID: 33946986
• DOI: 10.3390/cancers13092153

Front Mol Biosci. 2021 Apr 15;8:653073. doi: 10.3389/fmolb.2021.653073. eCollection 2021.

Bacterial Hsp90 Facilitates the Degradation of Aggregation-Prone Hsp70-Hsp40 Substrates

Bruno Fauvet ¹, Andrija Finka ², Marie-Pierre Castanié-Cornet ³, Anne-Marie Cirinesi ³, Pierre Genevaux ³, Manfredo Quadroni ⁴, Pierre Goloubinoff ¹Affiliations expand

Free PMC article

Abstract

In eukaryotes, the 90-kDa heat shock proteins (Hsp90s) are profusely studied chaperones that, together with 70-kDa heat shock proteins (Hsp70s), control protein homeostasis. In bacteria, however, the function of Hsp90 (HtpG) and its collaboration with Hsp70 (DnaK) remains poorly characterized. To uncover physiological processes that depend on HtpG and DnaK, we performed comparative quantitative proteomic analyses of insoluble and total protein fractions from unstressed wild-type (WT) Escherichia coli and from knockout mutants ΔdnaKdnaJ (ΔKJ), ΔhtpG (ΔG), and ΔdnaKdnaJΔhtpG (ΔKJG). Whereas the ΔG mutant showed no detectable proteomic differences with wild-type, ΔKJ expressed more chaperones, proteases and ribosomes and expressed dramatically less metabolic and respiratory enzymes. Unexpectedly, we found that the triple mutant ΔKJG showed higher levels of metabolic and respiratory enzymes than ΔKJ, suggesting that bacterial Hsp90 mediates the degradation of aggregation-prone Hsp70-Hsp40 substrates. Further in vivo experiments suggest that such Hsp90-mediated degradation possibly occurs through the HslUV protease.

Keywords: DnaJ; DnaK; HslV; HtpG; chaperones; proteostasis.

• PMID: 33937334
• PMCID: PMC8082187
• DOI: 10.3389/fmolb.2021.653073

Diabetes. 2021 Apr 21;db201121. doi: 10.2337/db20-1121. Online ahead of print.

Fgf15 neurons of the dorsomedial hypothalamus control glucagon secretion and hepatic gluconeogenesis

Alexandre Picard ¹, Salima Metref ¹, David Tarussio ¹, Wanda Dolci ¹, Xavier Berney ¹, Sophie Croizier ¹, Gwenaël Labouebe ¹, Bernard Thorens ²

Abstract

The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this gluco-regulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus, as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15CretdTomato mice and their use to further characterize these neurons. We showed that they were glutamatergic and comprised glucose inhibited and glucose excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the dorsomedial hypothalamus participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally-induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia.

© 2021 by the American Diabetes Association.

• PMID: 33883213
• DOI: 10.2337/db20-1121

Gut. 2021 Apr 26;gutjnl-2020-323323. doi: 10.1136/gutjnl-2020-323323. Online ahead of print.

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

Sarra Smati ^1 2, Arnaud Polizzi ¹, Anne Fougerat ¹, Sandrine Ellero-Simatos ¹, Yuna Blum ^3 4, Yannick Lippi ¹, Marion Régnier ¹, Alexia Laroyenne ¹, Marine Huillet ¹, Muhammad Arif ⁵, Cheng Zhang ⁵, Frederic Lasserre ¹, Alain Marrot ¹, Talal Al Saati ⁶, JingHong Wan ^7 8, Caroline Sommer ¹, Claire Naylies ¹, Aurelie Batut ², Celine Lukowicz ¹, Tiffany Fougeray ¹, Blandine Tramunt ², Patricia Dubot ^9 10, Lorraine Smith ¹, Justine Bertrand-Michel ², Nathalie Hennuyer ¹¹, Jean-Philippe Pradere ², Bart Staels ¹¹, Remy Burcelin ², Françoise Lenfant ², Jean-François Arnal ², Thierry Levade ^9 10, Laurence Gamet-Payrastre ¹, Sandrine Lagarrigue ¹², Nicolas Loiseau ¹, Sophie Lotersztajn ^7 8, Catherine Postic ¹³, Walter Wahli ^1 14 15, Christophe Bureau ¹⁶, Maeva Guillaume ¹⁶, Adil Mardinoglu ^5 17, Alexandra Montagner ², Pierre Gourdy ^# 18 19, Hervé Guillou ^# 20Affiliations expand

Abstract

Objective: We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.

Design: Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.

Results: The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.

Conclusions: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.

• PMID: 33903148
• DOI: 10.1136/gutjnl-2020-323323