Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis
John Zhong Li, … , Jonathan C. Cohen, Helen H. Hobbs
John Zhong Li, … , Jonathan C. Cohen, Helen H. Hobbs
Published October 1, 2012
Citation Information: J Clin Invest. 2012;122(11):4130-4144. https://doi.org/10.1172/JCI65179.
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Research Article Hepatology

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

Abstract

A genetic variant in PNPLA3 (PNPLA3I148M), 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 (PNPLA3WT) or mutant PNPLA3 (PNPLA3I148M) either in liver or adipose tissue. Overexpression of the transgenes in adipose tissue did not affect liver fat content. Expression of PNPLA3I148M, but not PNPLA3WT, 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 PNPLA3I148M 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 PNLPA3I148M 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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Figure 2

Increased hepatic TAG content in chow-fed PNPLA3I148M transgenic mice.

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Increased hepatic TAG content in chow-fed PNPLA3I148M transgenic mice. ...
(A) Liver sections from 12-week-old chow-fed wild-type (+/+) mice and PNPLA3WT and PNPLA3I148M transgenic male mice (n = 4/group) were stained with Oil Red O and viewed using a Leica microscope (DM2000) (original magnification, ×63). Hepatic lipid levels were measured in the same mice after a 4-hour fast. *P < 0.05. (B) Sections from adipose tissue of 12-week-old chow-fed wild-type mice and A-PNPLA3WT and A-PNPLA3I148M mice (n = 4/group) were stained with hematoxylin and eosin (top row). Images of BAT (original magnification, ×40) and WAT (original magnification, ×20) were taken. Hepatic lipid levels were measured after a 4-hour fast. Values are mean ± SEM (n = 4/group). Levels were compared among lines using Student’s t tests. The experiment was performed 3 times (n = 4–5 mice/group), and results were similar.