Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD.
Animals
Biomarkers
/ metabolism
Carnitine O-Palmitoyltransferase
/ genetics
Diabetes Mellitus
/ etiology
Diet, High-Fat
/ adverse effects
Disease Models, Animal
Fatty Acids
/ metabolism
Genetic Therapy
/ methods
Humans
Lipid Metabolism
Liver
/ metabolism
Male
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
/ etiology
Obesity
/ etiology
Oxidation-Reduction
Triglycerides
/ metabolism
AAV
CPT1A
fatty-acid oxidation
gene therapy
hepatic steatosis
lipid biomarker
obesity
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
22
03
2020
revised:
12
06
2020
accepted:
19
06
2020
pubmed:
16
7
2020
medline:
23
3
2021
entrez:
16
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32666604
doi: 10.1096/fj.202000678R
doi:
Substances chimiques
Biomarkers
0
Fatty Acids
0
Triglycerides
0
CPT1A protein, human
EC 2.3.1.21
Carnitine O-Palmitoyltransferase
EC 2.3.1.21
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11816-11837Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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