Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome.
PNPLA3 (adiponutrin, calcium-independent phospholipase A(2) epsilon [iPLA(2)ε]) is an adipose-enriched, nutritionally regulated protein that belongs to the patatin-like phospholipase domain containing (PNPLA) family of lipid metabolizing proteins. Genetic variations in the human PNPLA3 gene (i.e., the rs738409 I148M allele) has been strongly and repeatedly associated with fatty liver disease. Although human PNPLA3 has triacylglycerol (TAG) hydrolase and transacylase activities in vitro, its in vivo function and physiological relevance remain controversial. The objective of this study was to determine the metabolic consequences of global targeted deletion of the Pnpla3 gene in mice. We found that Pnpla3 mRNA expression is altered in adipose tissue and liver in response to acute and chronic nutritional challenges. However, global targeted deletion of the Pnpla3 gene in mice did not affect TAG hydrolysis, nor did it influence energy/glucose/lipid homoeostasis or hepatic steatosis/injury. Experimental interventions designed to increase Pnpla3 expression (refeeding, high-sucrose diet, diet-induced obesity, and liver X receptor agonism) likewise failed to reveal differences in the above-mentioned metabolic phenotypes. Expression of the Pnpla3 paralog, Pnpla5, was increased in adipose tissue but not in liver of Pnpla3-deficient mice, but compensatory regulation of genes involved in TAG metabolism was not identified. Together these data argue against a role for Pnpla3 loss-of-function in fatty liver disease or metabolic syndrome in mice.
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Mahesh K
MK
Basantani
Mitch T
MT
Sitnick
Lingzhi
L
Cai
Daniel S
DS
Brenner
Noah P
NP
Gardner
John Zhong
JZ
Li
Gabriele
G
Schoiswohl
Kui
K
Yang
Manju
M
Kumari
Richard W
RW
Gross
Rudolf
R
Zechner
Erin E
EE
Kershaw
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054512:Phospholipases A2, Calcium-Independent / Q000172:deficiency*; D014280:Triglycerides / Q000378:metabolism; D000217:Acyltransferases
D054512:Phospholipases A2, Calcium-Independent; D014280:Triglycerides; C549791:PNPLA3 protein, mouse; D000217:Acyltransferases