PMID- 21319201
OWN - NLM
STAT- MEDLINE
DCOM- 20110512
LR  - 20130520
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 53
IP  - 3
DP  - 2011 Mar
TI  - Molecular therapy for obesity and diabetes based on a long-term increase in 
      hepatic fatty-acid oxidation.
PG  - 821-32
LID - 10.1002/hep.24140 [doi]
AB  - Obesity-induced insulin resistance is associated with both ectopic lipid 
      deposition and chronic, low-grade adipose tissue inflammation. Despite their 
      excess fat, obese individuals show lower fatty-acid oxidation (FAO) rates. This 
      has raised the question of whether burning off the excess fat could improve the 
      obese metabolic phenotype. Here we used human-safe nonimmunoreactive 
      adeno-associated viruses (AAV) to mediate long-term hepatic gene transfer of 
      carnitine palmitoyltransferase 1A (CPT1A), the key enzyme in fatty-acid 
      beta-oxidation, or its permanently active mutant form CPT1AM, to high-fat 
      diet-treated and genetically obese mice. High-fat diet CPT1A- and, to a greater 
      extent, CPT1AM-expressing mice showed an enhanced hepatic FAO which resulted in 
      increased production of CO(2) , adenosine triphosphate, and ketone bodies. 
      Notably, the increase in hepatic FAO not only reduced liver triacylglyceride 
      content, inflammation, and reactive oxygen species levels but also systemically 
      affected a decrease in epididymal adipose tissue weight and inflammation and 
      improved insulin signaling in liver, adipose tissue, and muscle. Obesity-induced 
      weight gain, increase in fasting blood glucose and insulin levels, and augmented 
      expression of gluconeogenic genes were restored to normal only 3 months after AAV 
      treatment. Thus, CPT1A- and, to a greater extent, CPT1AM-expressing mice were 
      protected against obesity-induced weight gain, hepatic steatosis, diabetes, and 
      obesity-induced insulin resistance. In addition, genetically obese db/db mice 
      that expressed CPT1AM showed reduced glucose and insulin levels and liver 
      steatosis. CONCLUSION: A chronic increase in liver FAO improves the obese 
      metabolic phenotype, which indicates that AAV-mediated CPT1A expression could be 
      a potential molecular therapy for obesity and diabetes.
CI  - Copyright (c) 2010 American Association for the Study of Liver Diseases.
FAU - Orellana-Gavalda, Josep M
AU  - Orellana-Gavalda JM
AD  - Department of Biochemistry and Molecular Biology, Institut de Biomedicina de la 
      Universitat de Barcelona (IBUB), Barcelona, Spain.
FAU - Herrero, Laura
AU  - Herrero L
FAU - Malandrino, Maria Ida
AU  - Malandrino MI
FAU - Paneda, Astrid
AU  - Paneda A
FAU - Sol Rodriguez-Pena, Maria
AU  - Sol Rodriguez-Pena M
FAU - Petry, Harald
AU  - Petry H
FAU - Asins, Guillermina
AU  - Asins G
FAU - Van Deventer, Sander
AU  - Van Deventer S
FAU - Hegardt, Fausto G
AU  - Hegardt FG
FAU - Serra, Dolors
AU  - Serra D
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110211
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Dietary Fats)
RN  - 0 (Fatty Acids)
RN  - 0 (Triglycerides)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
CIN - Hepatology. 2011 Jun;53(6):2143-4; author reply 2145-6. PMID: 21433038
CIN - Hepatology. 2011 Sep 2;54(3):1110-1. PMID: 21488073
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/*administration & dosage/genetics
MH  - Dependovirus/genetics
MH  - Diabetes Mellitus/*therapy
MH  - Dietary Fats/administration & dosage
MH  - Fatty Acids/*metabolism
MH  - Fatty Liver/metabolism/therapy
MH  - Genetic Therapy
MH  - Humans
MH  - Insulin Resistance/physiology
MH  - Liver/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Obese
MH  - Obesity/complications/*therapy
MH  - Oxidation-Reduction
MH  - Triglycerides/metabolism
EDAT- 2011/02/15 06:00
MHDA- 2011/05/13 06:00
CRDT- 2011/02/15 06:00
PHST- 2010/10/25 00:00 [received]
PHST- 2010/12/12 00:00 [accepted]
PHST- 2011/02/15 06:00 [entrez]
PHST- 2011/02/15 06:00 [pubmed]
PHST- 2011/05/13 06:00 [medline]
AID - 10.1002/hep.24140 [doi]
PST - ppublish
SO  - Hepatology. 2011 Mar;53(3):821-32. doi: 10.1002/hep.24140. Epub 2011 Feb 11.