The polymorphism is more common in those of Southern European anc

The polymorphism is more common in those of Southern European ancestry.15 It is not associated with higher frequency of obesity or insulin resistance, but among the overweight it correlates closely with central obesity (waist circumference) and hepatic steatosis (mass resonance spectrometry).13 In Dallas, TX, rs738409G accounts for virtually all the ethnic differences in NAFLD frequency, from ∼40% in Hispanics, through ∼30% in Europeans, to ∼20% for African Americans.13 The PNPLA3 polymorphism buy Alvelestat also correlates with raised serum alanine aminotransferase,15–17 indicating predilection to liver injury in subjects with NAFLD,

and it has now been linked to higher rates of NASH,18 and fibrosis

with NAFLD and alcoholic liver disease.18, 19 One might anticipate that knowing how PNPLA3 mutation is related to hepatic lipid distribution and liver injury would give profound insights into the pathogenesis of NASH. Unfortunately, information about the location (adipose or liver) and regulated roles of PNPLA3 in TG synthesis and lipolysis remains fragmentary and ambiguous.7, 15, 20 Although predominantly expressed in adipose, it is also present in liver, more so in humans than mice.20 PNPLA3 was discovered in the search for more complete understanding 5-Fluoracil molecular weight of TG turnover. Earlier attention had focused on hormone-suppressible lipase which catalyzes hydrolysis of diacylglycerol, the second step in TG lipolysis, and mono-acylglyceride lipase, which with its coregulator, comparative gene identification-58, catalyzes the third step.7 The first step is catalyzed by acyltriglyceride lipase (ATGL) (adiponutrin 2).7 The adiponutrins seem to play cooperative roles in both lipolysis and its opposite

process of transacylation during TG synthesis.7, 15, 20 PNPLA3 expression is suppressed by fasting and induced by a carbohydrate-rich diet; it may therefore be involved with TG synthesis and storage during times of energy excess. Its strong regulation selleckchem by insulin (via SREBP1) accords with that function.15, 20 In the early stages of NAFLD pathogenesis, when partial IR activates SREBP1,1 PNPLA3, acting as a transacylation pathway in lipogenesis, could play a role in expanding adipose TG stores, but it is unclear whether this differs between SAT and VAT, or whether defective PNPLA3 would liberate more FFA to be taken up by the liver (Fig. 1). Conversely, if the main function of PNPLA3 is to regulate lipolysis, its inactivity would favor TG accumulation, which is desirable in adipose, but potentially increases TG storage in liver.

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