Lipid sensing by PPARα: Role in controlling hepatocyte gene regulatory networks and the metabolic response to fasting

Anne Fougerat ¹, Justine Bruse ², Arnaud Polizzi ², Alexandra Montagner ³, Hervé Guillou ², Walter Wahli ⁴

 Epub 2024 Nov 7.

• PMID: 39521352
• DOI: 10.1016/j.plipres.2024.101303

Free article

Abstract

Peroxisome proliferator-activated receptors (PPARs) constitute a small family of three nuclear receptors that act as lipid sensors, and thereby regulate the transcription of genes having key roles in hepatic and whole-body energy homeostasis, and in other processes (e.g., inflammation), which have far-reaching health consequences. Peroxisome proliferator-activated receptor isotype α (PPARα) is expressed in oxidative tissues, particularly in the liver, carrying out critical functions during the adaptive fasting response. Advanced omics technologies have provided insight into the vast complexity of the regulation of PPAR expression and activity, as well as their downstream effects on the physiology of the liver and its associated metabolic organs. Here, we provide an overview of the gene regulatory networks controlled by PPARα in the liver in response to fasting. We discuss impacts on liver metabolism, the systemic repercussions and benefits of PPARα-regulated ketogenesis and production of fibroblast growth factor 21 (FGF21), a fasting- and stress-inducible metabolic hormone. We also highlight current challenges in using novel methods to further improve our knowledge of PPARα in health and disease.

Circadian plasticity evolves through regulatory changes in a neuropeptide gene

Michael P Shahandeh ^1 2, Liliane Abuin ³, Lou Lescuyer De Decker ³, Julien Cergneux ³, Rafael Koch ⁴, Emi Nagoshi ⁴, Richard Benton ⁵

Affiliations Expand

• PMID: 39415010
• PMCID: PMC11602725
• DOI: 10.1038/s41586-024-08056-x

Abstract

Many organisms, including cosmopolitan drosophilids, show circadian plasticity, varying their activity with changing dawn-dusk intervals¹. How this behaviour evolves is unclear. Here we compare Drosophila melanogaster with Drosophila sechellia, an equatorial, ecological specialist that experiences minimal photoperiod variation, to investigate the mechanistic basis of circadian plasticity evolution². D. sechellia has lost the ability to delay its evening activity peak time under long photoperiods. Screening of circadian mutants in D. melanogaster/D. sechellia hybrids identifies a contribution of the neuropeptide pigment-dispersing factor (Pdf) to this loss. Pdf exhibits species-specific temporal expression, due in part to cis-regulatory divergence. RNA interference and rescue experiments in D. melanogaster using species-specific Pdf regulatory sequences demonstrate that modulation of this neuropeptide’s expression affects the degree of behavioural plasticity. The Pdf regulatory region exhibits signals of selection in D. sechellia and across populations of D. melanogaster from different latitudes. We provide evidence that plasticity confers a selective advantage for D. melanogaster at elevated latitude, whereas D. sechellia probably suffers fitness costs through reduced copulation success outside its range. Our findings highlight this neuropeptide gene as a hotspot locus for circadian plasticity evolution that might have contributed to both D. melanogaster’s global distribution and D. sechellia’s specialization.

Increased hepatic gluconeogenesis and type 2 diabetes mellitus

Emma Barroso ¹, Javier Jurado-Aguilar ¹, Walter Wahli ², Xavier Palomer ¹, Manuel Vázquez-Carrera ³

. 2024 Dec;35(12):1062-1077.

• PMID: 38816269
• DOI: 10.1016/j.tem.2024.05.006

Abstract

Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.

Transcriptional and functional regulation of cell cycle and UV response by PPARβ in human skin epidermal cells

Thanh Nhan Nguyen ¹, Carine Winkler ¹, Stefanie Ginster ¹, Stéphanie Claudinot ¹, Liliane Michalik ¹, Paris Jafari ¹

. 2024 Dec 15;38(23):e70212.

• PMID: 39620966
• PMCID: PMC11610672
• DOI: 10.1096/fj.202401950R

Abstract

Solar radiation is the main source of human exposure to UV rays, which is the major carcinogen in skin cancers by inducing DNA damage. Skin cells repair these damages by activating the DNA damage response (DDR) to safeguard genome integrity, thereby preventing skin cancers. Peroxisome proliferator-activated receptor beta (PPARβ), a druggable transcription factor, is involved in the development of UV-dependent skin cancers, although its role is not mechanistically elucidated. We showed previously that PPARβ knockout (KO) mice are less prone to UV-induced skin cancers. Here, we report that PPARβ directly regulates gene expression programs associated with cell cycle and DNA repair pathways in normal human epidermal keratinocytes (NHEK). The loss of function of PPARβ in human keratinocytes led to a downregulation in the expression of key cell cycle regulators, including cyclins and cyclin-dependent kinases (CDKs). Simultaneously, it upregulated the expression of p21 protein, a known CDK inhibitor. These molecular alterations resulted in a significant reduction in cell proliferation and induced cell cycle arrest at the G2/M phase. Moreover, the absence of functional PPARβ disrupted the expression and activation of the ataxia telangiectasia and Rad3-related (ATR) pathway, a critical component of the cellular response to UV-induced DNA damage. The alterations in the ATR pathway likely contributed to an increased apoptotic response of NHEK to UV radiation. Using a mouse melanoma model, we demonstrated that the depletion of PPARβ decreases tumorigenicity of melanoma cells and delays tumor formation. Our data suggest that PPARβ inhibition could be considered as a therapeutic target for the prevention of UV-induced skin cancers, by regulating cell proliferation, attenuating DDR, and eliminating skin cells with high UV-induced mutational burden.

Further delineation of the SCAF4-associated neurodevelopmental disorder

Cosima M Schmid ^1 2, Anne Gregor ^1 2, Anna Ruiz ³, Carmen Manso Bazús ³, Isabella Herman ^4 5 6, Farah Ammouri ⁷, Urania Kotzaeridou ⁸, Vanda McNiven ⁹, Lucie Dupuis ¹⁰, Katharina Steindl ¹¹, Anaïs Begemann ¹¹, Anita Rauch ¹¹, Aude-Annick Suter ¹¹, Bertrand Isidor ¹², Sandra Mercier ¹², Mathilde Nizon ¹², Benjamin Cogné ¹², Wallid Deb ¹², Thomas Besnard ¹², Tobias B Haack ^13 14, Ruth J Falb ¹³, Amelie J Müller ¹³, Tobias Linden ¹⁵, Chad R Haldeman-Englert ¹⁶, Charlotte W Ockeloen ¹⁷, Francesca Mattioli ¹⁸, Alexandre Reymond ¹⁸, Nazia Ibrahim ¹⁹, Shagufta Naz ¹⁹, Elodie Lacaze ²⁰, Jennifer A Bassetti ²¹, Julia Hoefele ²², Theresa Brunet ²², Korbinian M Riedhammer ^22 23, Houda Z Elloumi ²⁴, Richard Person ²⁴, Fanggeng Zou ²⁴, Juliette J Kahle ²⁴, Kirsten Cremer ²⁵, Axel Schmidt ²⁵, Marie-Ange Delrue ²⁶, Pedro M Almeida ²⁷, Fabiana Ramos ^27 28, Siddharth Srivastava ²⁹, Aisling Quinlan ²⁹, Stephen Robertson ³⁰, Eva Manka ³¹, Alma Kuechler ³², Stephanie Spranger ³³, Malgorzata J M Nowaczyk ³⁴, Reem M Elshafie ³⁵, Hind Alsharhan ^35 36, Paul R Hillman ³⁷, Leslie A Dunnington ³⁷, Hilde M H Braakman ³⁸, Shane McKee ³⁹, Angelica Moresco ⁴⁰, Andrea-Diana Ignat ⁴⁰, Ruth Newbury-Ecob ⁴¹, Guillaume Banneau ⁴², Olivier Patat ⁴², Jeffrey Kuerbitz ^6 43, Susan Rzucidlo ⁴⁴, Susan S Sell ⁴⁴, Patricia Gordon ⁴⁴, Sarah Schuhmann ⁴⁵, André Reis ^45 46, Yosra Halleb ⁴⁷, Radka Stoeva ⁴⁷, Boris Keren ⁴⁸, Zainab Al Masseri ⁴⁹, Zeynep Tümer ^50 51, Sophia Hammer-Hansen ⁵², Sofus Krüger Sølyst ⁵², Connolly G Steigerwald ⁵³, Nicolas J Abreu ⁵³, Helene Faust ⁵⁴, Amica Müller-Nedebock ⁵⁴, Frédéric Tran Mau-Them ^55 56, Heinrich Sticht ⁵⁷, Christiane Zweier ^58 59

. 2024 Dec 12.

 doi: 10.1038/s41431-024-01760-2. Online ahead of print.

• PMID: 39668183
• DOI: 10.1038/s41431-024-01760-2

Abstract

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of SCAF4 variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.

PPARβ/δ prevents inflammation and fibrosis during diabetic cardiomyopathy

Adel Rostami ¹, Xavier Palomer ², Javier Pizarro-Delgado ¹, Emma Barroso ¹, Brenda Valenzuela-Alcaraz ³, Fátima Crispi ³, J Francisco Nistal ⁴, María A Hurlé ⁵, Raquel García ⁵, Walter Wahli ⁶, Manuel Vázquez-Carrera ⁷

Affiliations Expand

• PMID: 39577755
• DOI: 10.1016/j.phrs.2024.107515

Free article

Abstract

Diabetic cardiomyopathy (DCM) is a specific type of myocardial disease that often develops in patients suffering from diabetes, which has become the foremost cause of death among them. It is an insidious multifactorial disease caused by complex and partially unknown mechanisms that include metabolic dysregulation, local inflammation, fibrosis, and cardiomyocyte apoptosis. Despite its severity and poor prognosis, it often goes undiagnosed, and there are currently no approved specific drugs to prevent or even treat it. Peroxisome proliferator-activated receptor (PPAR)β/δ is a key metabolic regulator that has been proposed as a potential target for DCM due to its pleiotropic anti-inflammatory properties. Diabetes was induced by multiple low-dose streptozotocin (STZ) administration in wild-type and PPARβ/δ knockout male mice treated with the PPARβ/δ agonist GW0742 or vehicle. Human cardiomyocytes (AC16) and mouse atrial myocytes (HL-1) exposed to hyperglycemia and treated with PPARβ/δ agonists were also used. PPARβ/δ deletion in mice negatively impacted cardiac morphology and function, which was accompanied by interstitial fibrosis and structural remodeling of the heart. This phenotype was further exacerbated in knockout diabetic mice. At the molecular level, PPARβ/δ suppression resulted in increased expression of pro-inflammatory and pro-fibrotic markers. Some of these markers were also induced by diabetes in wild-type mice and were exacerbated in diabetic knockout mice. The activity of the transcription factors nuclear factor κB (NF-κB) and activator protein-1 (AP-1) correlated with most of these changes. Remarkably, PPARβ/δ activation partially prevented inflammation and fibrosis in the heart, as well as cardiac atrophy, induced during diabetes in mice, and also in cultured cardiomyocytes exposed to hyperglycemia. Finally, our results suggest that the beneficial effects of PPARβ/δ activation are mediated by the inhibition of mitogen-activated protein kinases (MAPK) activity and subsequent downregulation of the transcriptional activities of NF-κB and AP-1. Overall, the data suggest that PPARβ/δ agonists might be useful in preventing inflammation and fibrosis progression in DCM.