Weber 2020 FASEB J
|Weber M, Mera P, Casas J, Salvador J, Rodríguez A, Alonso S, Sebastián D, Soler-Vázquez MC, Montironi C, Recalde S, Fucho R, Calderón-Domínguez M, Mir JF, Bartrons R, Escola-Gil JC, Sánchez-Infantes D, Zorzano A, Llorente-Cortes V, Casals N, Valentí V, Frühbeck G, Herrero L, Serra D (2020) Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD. FASEB J [Epub ahead of print].|
Weber Mineia, Mera Paula, Casas Josefina, Salvador Javier, Rodriguez Amaia, Alonso Sergio, Sebastian David, Soler-Vazquez M Carmen, Montironi Carla, Recalde Sandra, Fucho Raquel, Calderón-Domínguez Maria, Mir Joan Francesc, Bartrons Ramon, Escola-Gil Joan Carles, Sanchez-Infantes David, Zorzano Antonio, Llorente-Cortes Vicenta, Casals Nuria, Valenti Victor, Fruehbeck Gema, Herrero Laura, Serra Dolors (2020) FASEB J
Abstract: The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.
Labels: MiParea: Respiration, nDNA;cell genetics Pathology: Obesity
Organism: Mouse Tissue;cell: Liver Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: N, NS HRR: Oxygraph-2k