Document Detail


Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis.
MedLine Citation:
PMID:  23023705     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A genetic variant in PNPLA3 (PNPLA3(I148M)), a triacylglycerol (TAG) hydrolase, is a major risk factor for nonalcoholic fatty liver disease (NAFLD); however, the mechanism underlying this association is not known. To develop an animal model of PNPLA3-induced fatty liver disease, we generated transgenic mice that overexpress similar amounts of wild-type PNPLA3 (PNPLA3(WT)) or mutant PNPLA3 (PNPLA3(I148M)) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3(I148M), but not PNPLA3(WT), in liver recapitulated the fatty liver phenotype as well as other metabolic features associated with this allele in humans. Metabolic studies provided evidence for 3 distinct alterations in hepatic TAG metabolism in PNPLA3(I148M) transgenic mice: increased formation of fatty acids and TAG, impaired hydrolysis of TAG, and relative depletion of TAG long-chain polyunsaturated fatty acids. These findings suggest that PNPLA3 plays a role in remodeling TAG in lipid droplets, as they accumulate in response to food intake, and that the increase in hepatic TAG levels associated with the I148M substitution results from multiple changes in hepatic TAG metabolism. The development of an animal model that recapitulates the metabolic phenotype of the allele in humans provides a new platform in which to elucidate the role of PNLPA3(I148M) in NAFLD.
Authors:
John Zhong Li; Yongcheng Huang; Ruchan Karaman; Pavlina T Ivanova; H Alex Brown; Thomas Roddy; Jose Castro-Perez; Jonathan C Cohen; Helen H Hobbs
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-12-26     Completed Date:  2013-01-15     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4130-44     Citation Subset:  AIM; IM    
Affiliation:
Department of Molecular Genetics, Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA, USA.
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MeSH Terms
Descriptor/Qualifier:
Adipose Tissue / enzymology,  pathology
Amino Acid Substitution
Animals
Fatty Acids / genetics,  metabolism
Fatty Liver / enzymology*,  genetics,  pathology
Humans
Lipid Metabolism*
Liver / enzymology*,  pathology
Mice
Mice, Transgenic
Mutation, Missense*
Phospholipases A2, Calcium-Independent / biosynthesis*,  genetics
Triglycerides / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
1HL092550/HL/NHLBI NIH HHS; DK090066/DK/NIDDK NIH HHS; GM 069338/GM/NIGMS NIH HHS; HL20948/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Triglycerides; EC 3.1.1.3/PNPLA3 protein, mouse; EC 3.1.1.4/Phospholipases A2, Calcium-Independent
Comments/Corrections

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