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

Abstract

Obesity and the metabolic syndrome are major contributors to morbidity and mortality from a variety of diseases affecting virtually all organ systems ( 1 ). Obesity is essentially a disorder of lipid accumulation, primarily in the form of triacylglycerols (TAGs) in adipose tissue. TAGs serve as a critical reservoir for lipid metabolites involved not only in energy homeostasis but also other essential cellular processes including membrane synthesis and cell signaling. 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 Abstract PNPLA3 (adiponutrin, calcium-independent phospholipase A 2 epsilon [iPLA 2 ]) is an adipose-enriched, nutritionally regulated protein that belongs to the patatinlike 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 infl uence 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 -defi cient mice, but compensatory regulation of genes involved in TAG metabolism was not identifi ed. Together these data argue against a role for Pnpla3 loss-of-function in fatty liver disease or metabolic syndrome in mice. -Basantani,

PNPLA3 gene in liver diseases

“…This could suggest a gain of function and a lipogenic role for PNPLA3 that would be enhanced by the presence of the I148M mutation. In addition, other studies performed in PNPLA3 knockout mice did not advocate for a major role of PNPLA3 in steatosis accumulation [83,84]. Thus, PNPLA3 À/À mice did not significantly differ from WT, fed a specific regimen or not, for body weight, adipose mass/ development, insulin sensitivity, or glucose tolerance.…”

Diet-induced obesity affects expression of adiponutrin/PNPLA3 and adipose triglyceride lipase, two members of the same family

“…2,[8][9][10] In vitro suppression or overexpression of adiponutrin in adipocytes, as well as its global targeted deletion in mice, does not affect triacylglycerol content or energy homeostasis. 8,11,12 Thus, although it can have lipolytic/ lipogenic capacity, the function of this protein remains unclear. However, adiponutrin nutritional regulation supports a role in the maintenance of energy homeostasis through lipogenic processes rather than a lipase activity, promoting adipocyte energy storage in situations of energy excess.…”

“…Anyway, recent data obtained with mice lacking the adiponutrin gene do not evidence the presence of hepatic steatosis or injury in these animals. 12 The physiological role of ATGL, also known as PNPLA2 and desnutrin, is mostly clear. The protein hydrolyzes longchain fatty acid triacylglycerols to diacylglycerols in a fasting situation, providing the substrate for hormone-sensitive lipase in the lipolytic cascade.…”

Identification of eQTLs for hepatic Xbp1 s and Socs3 gene expression in mice fed a high-fat, high caloric diet

“…This polymorphism has subsequently been associated with the severity of NASH, liver stiffness, fibrosis, and potentially hepatocellular carcinoma. Overexpression of the PNPLA3 I148M polymorphism in mice also causes hepatic steatosis and PNPLA3 has been shown to regulate hepatic lipid metabolism (Basantani et al 2011;Chen et al 2010;Li et al 2012;Ruhanen et al 2014;Singal et al 2014;Said 2013;Pingitore et al 2014;Krawczyk et al 2013;Peng et al 2012;Santoro et al 2010;Rotman et al n Figure 4 Hepatic mRNA expression of Xbp1s and Socs3 in A/J, C57BL/6J, and C57BL/6J-Chr 1A/J/ NaJ and C57BL/6J-Chr 11A/J/NaJ mice. Male A/J, C57BL/6J, C57BL/6J-Chr 1A/J/NaJ, and C57BL/6J-Chr 11A/J/NaJ mice were fed a 60% high-fat, highcaloric (HFHC) diet for 8 wk and hepatic mRNA expression of (A) Xbp1s and (B) Socs3 gene expression measured using RT-PCR.…”