Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

Mahesh K. Basantani, Mitch T. Sitnick, Lingzhi Cai, Daniel S. Brenner, Noah P. Gardner, John Zhong Li, Gabriele Schoiswohl, Kui Yang, Manju Kumari, Richard W. Gross, Rudolf Zechner, Erin E. Kershaw

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131 Citations (Scopus)

Abstract

PNPLA3 (adiponutrin, calcium-independent phospholipase A2 epsilon [iPLA2ε]) 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.

Original languageEnglish
Pages (from-to)318-329
Number of pages12
JournalJournal of Lipid Research
Volume52
Issue number2
DOIs
StatePublished - 1 Feb 2011

Fingerprint

Fatty Liver
Liver
Liver Diseases
Genes
Gene Deletion
Adipose Tissue
Nutrition
Calcium-Independent Phospholipase A2
Triglycerides
Diet
Lipids
Phospholipases
Tissue
Lipase
Sucrose
Proteins
Hydrolysis
Homeostasis
Metabolism
Obesity

Keywords

  • Calcium-independent phospholipase A epsilon
  • Insulin resistance
  • Patatin-like phospholipase domain-containing 3

Cite this

Basantani, Mahesh K. ; Sitnick, Mitch T. ; Cai, Lingzhi ; Brenner, Daniel S. ; Gardner, Noah P. ; Li, John Zhong ; Schoiswohl, Gabriele ; Yang, Kui ; Kumari, Manju ; Gross, Richard W. ; Zechner, Rudolf ; Kershaw, Erin E. / Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. In: Journal of Lipid Research. 2011 ; Vol. 52, No. 2. pp. 318-329.
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abstract = "PNPLA3 (adiponutrin, calcium-independent phospholipase A2 epsilon [iPLA2ε]) 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.",
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author = "Basantani, {Mahesh K.} and Sitnick, {Mitch T.} and Lingzhi Cai and Brenner, {Daniel S.} and Gardner, {Noah P.} and Li, {John Zhong} and Gabriele Schoiswohl and Kui Yang and Manju Kumari and Gross, {Richard W.} and Rudolf Zechner and Kershaw, {Erin E.}",
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Basantani, MK, Sitnick, MT, Cai, L, Brenner, DS, Gardner, NP, Li, JZ, Schoiswohl, G, Yang, K, Kumari, M, Gross, RW, Zechner, R & Kershaw, EE 2011, 'Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome', Journal of Lipid Research, vol. 52, no. 2, pp. 318-329. https://doi.org/10.1194/jlr.M011205

Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. / Basantani, Mahesh K.; Sitnick, Mitch T.; Cai, Lingzhi; Brenner, Daniel S.; Gardner, Noah P.; Li, John Zhong; Schoiswohl, Gabriele; Yang, Kui; Kumari, Manju; Gross, Richard W.; Zechner, Rudolf; Kershaw, Erin E.

In: Journal of Lipid Research, Vol. 52, No. 2, 01.02.2011, p. 318-329.

Research output: Contribution to journalArticle

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T1 - Pnpla3/adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

AU - Basantani, Mahesh K.

AU - Sitnick, Mitch T.

AU - Cai, Lingzhi

AU - Brenner, Daniel S.

AU - Gardner, Noah P.

AU - Li, John Zhong

AU - Schoiswohl, Gabriele

AU - Yang, Kui

AU - Kumari, Manju

AU - Gross, Richard W.

AU - Zechner, Rudolf

AU - Kershaw, Erin E.

PY - 2011/2/1

Y1 - 2011/2/1

N2 - PNPLA3 (adiponutrin, calcium-independent phospholipase A2 epsilon [iPLA2ε]) 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.

AB - PNPLA3 (adiponutrin, calcium-independent phospholipase A2 epsilon [iPLA2ε]) 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.

KW - Calcium-independent phospholipase A epsilon

KW - Insulin resistance

KW - Patatin-like phospholipase domain-containing 3

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