Abstract
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.
Highlights
PNPLA3 is an adipose-enriched, nutritionally regulated protein that belongs to the patatinlike phospholipase domain containing (PNPLA) family of lipid metabolizing proteins
To identify genes and/or pathways that might be compensating for Pnpla3 deficiency, we evaluated mRNA expression of genes involved in TAG metabolism in liver and perigonadal white adipose tissue (WAT) of ad libitum-fed WT and Pnpla3KO mice fed chow or an low-fat low-sucrose (LFLS), low-fat high-sucrose (LFHS), or high-fat high-sucrose (HFHS) diet from weaning until 19 weeks of age (Fig. 7 and supplemental Table I)
Substantial data support an important role for PNPLA3 in normal metabolism and disease including the following: i) PNPLA3 shares significant homology with proteins known to play critical roles in metabolism [9, 64, 65]; ii) PNPLA3 is highly regulated by important nutritional/metabolic factors [25, 27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]; iii) PNPLA3 expression is altered in obese/dysmetabolic states [25, 27,28,29]; iv) PNPLA3 has lipid hydrolase and transacylase activities in vitro [28, 43, 44]; and v) Genetic variation in PNPLA3 is associated with nonalcoholic fatty liver disease (NAFLD) in humans [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]
Summary
PNPLA3 (adiponutrin, calcium-independent phospholipase A2 epsilon [iPLA2]) is an adipose-enriched, nutritionally regulated protein that belongs to the patatinlike phospholipase domain containing (PNPLA) family of lipid metabolizing proteins. Global targeted deletion of the Pnpla gene in mice did not affect TAG hydrolysis, nor did it influence energy/glucose/lipid homoeostasis or hepatic steatosis/injury. Expression of the Pnpla paralog, Pnpla, was increased in adipose tissue but not in liver of Pnpla3deficient mice, but compensatory regulation of genes involved in TAG metabolism was not identified. Together these data argue against a role for Pnpla loss-of-function in fatty liver disease or metabolic syndrome in mice.—Basantani, M. In the context of chronic energy excess and/or impaired lipid metabolism, TAGs accumulate in metabolically relevant nonadipose tissues such as liver, where they are associated with cellular and systemic. The mechanisms underlying hepatocellular TAG accumulation and its relationship to lipid-induced toxic metabolic effects (lipotoxicity) remain unclear
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