Liver CPT1A gene therapy reduces diet‐induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

Here we show for the first time that liver human isoform of CPT1AM gene therapy in a mouse model of established obesity, diabetes, and nonalcoholic fatty liver disease can reduce high-fat diet -induced derangements

Minéia Weber; Paula Mera; Josefina Casas; Javier Salvador; Amaia Rodríguez; Sergio Alonso; David Sebastián; M. Carmen Soler‐Vázquez; Carla Montironi; Sandra Recalde; Raquel Fucho; María Calderón‐Domínguez; Joan Francesc Mir; Ramon Bartrons; Joan Carles Escola‐Gil; David Sánchez‐Infantes; Antonio Zorzano; Vicenta Llorente‐Cortes; Núria Casals; Víctor Valentí; Gema Frühbeck; Laura Herrero; Dolors Serra

2020

Scholarcy highlights

  • Despite enormous efforts by health-care providers and the research community, obesity rates continue to rise
  • We focused on three novel strategies: use of the AAV9 serotype, which is the most effective associated virus in gene therapy at targeting liver; use of a mouse model with established obesity, type 2 diabetes, and nonalcoholic fatty liver disease; and use of the human isoform of CPT1AM, with the prospect of future clinical therapeutic applications
  • Our results show that enhanced hepatic fatty acid oxidation through human isoform of CPT1AM-mediated gene therapy reduces diet-induced weight gain, and hepatic steatosis and improves hepatic insulin signaling in obese mice
  • Because the expression of hCPT1AM in the liver of HFDfed mice decreases the accumulation of lipid droplets, we examined the two main catabolic pathways of LDs: lipolysis and autophagy
  • Here we describe that AAV9-mediated hCPT1AM-expressing mice under high-fat diet showed increased liver FAO and, importantly, reduced NAFLD and improved glucose tolerance and hepatic insulin signaling compared to HFD-fed control mice
  • Hepatic hCPT1AM-expression in HFD-fed mice is sufficient to reduce potentially toxic lipid intermediates in the liver, such as DAG and ceramides, that can activate protein kinase C resulting in an impairment in the insulin signaling pathway. These reduced ceramides and DAGs levels could explain the enhanced hepatic insulin signaling observed in HFD-hCPT1AM mice
  • Here we report an efficient gene therapy approach to greatly reduce liver steatosis and body weight and to improve glucose tolerance and hepatic insulin signaling in a mouse model of high-fat diet-induced obesity

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