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fat content, a 3.2-fold greater risk of high necroinflammatory scores and a 3.2-fold greater risk of
developing fibrosis [4]. PNPLA3 is predominantly expressed in the liver. In vitro studies with purified
human PNPLA3 have shown that the wild-type enzyme hydrolyses triglycerides and that the Ile148Met
substitution abolishes this activity. These data suggest that the Ile148Met substitution is a loss-of-
function mutation that impairs triglyceride hydrolysis. IR is not a feature of NAFLD associated with the
PNPLA3 rs738409[G], although, given the high prevalence of obesity/MetS, many subjects carrying the
variant also have the MetS [2]. Subjects with NAFLD carrying the PNPLA I148M gene variant (20-50%
of all subjects with NAFLD) have an increased liver fat content but a similar cardiovascular risk profile
than non-carriers. This implies that the increased risk of CVD characterizing subjects with NAFLD is
not due to steatosis per se.These data suggest that genotyping for the I148M variant in PNPLA3 might
identify subjects who are at increased risk of hepatic but not cardiovascular complications.
References
[1] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim
statement of the International Diabetes Federation Task Force on Epidemiology and Prevention;
National Heart, Lung, and Blood Institute; American Heart Association;World Heart Federation;
International Atherosclerosis Society; and International Association for the Study of Obesity.
Circulation 2009;120:1640-1645.
[2] Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic
syndrome. Lancet Diabetes Endocrinol 2014;2:901-910.
[3] Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular
disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013;10:330-344.
[4] Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase
domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic
fatty liver disease. Hepatology 2011;53:1883-1894.
58 Postgraduate Course Syllabus • Metabolic Liver Disease
developing fibrosis [4]. PNPLA3 is predominantly expressed in the liver. In vitro studies with purified
human PNPLA3 have shown that the wild-type enzyme hydrolyses triglycerides and that the Ile148Met
substitution abolishes this activity. These data suggest that the Ile148Met substitution is a loss-of-
function mutation that impairs triglyceride hydrolysis. IR is not a feature of NAFLD associated with the
PNPLA3 rs738409[G], although, given the high prevalence of obesity/MetS, many subjects carrying the
variant also have the MetS [2]. Subjects with NAFLD carrying the PNPLA I148M gene variant (20-50%
of all subjects with NAFLD) have an increased liver fat content but a similar cardiovascular risk profile
than non-carriers. This implies that the increased risk of CVD characterizing subjects with NAFLD is
not due to steatosis per se.These data suggest that genotyping for the I148M variant in PNPLA3 might
identify subjects who are at increased risk of hepatic but not cardiovascular complications.
References
[1] Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim
statement of the International Diabetes Federation Task Force on Epidemiology and Prevention;
National Heart, Lung, and Blood Institute; American Heart Association;World Heart Federation;
International Atherosclerosis Society; and International Association for the Study of Obesity.
Circulation 2009;120:1640-1645.
[2] Yki-Jarvinen H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic
syndrome. Lancet Diabetes Endocrinol 2014;2:901-910.
[3] Anstee QM, Targher G, Day CP. Progression of NAFLD to diabetes mellitus, cardiovascular
disease or cirrhosis. Nat Rev Gastroenterol Hepatol 2013;10:330-344.
[4] Sookoian S, Pirola CJ. Meta-analysis of the influence of I148M variant of patatin-like phospholipase
domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic
fatty liver disease. Hepatology 2011;53:1883-1894.
58 Postgraduate Course Syllabus • Metabolic Liver Disease
