Studying nonalcoholic fatty liver disease with ze

Authors: Amnon Schlegel

Publish Date: 2012/06/08

Volume: 69, Issue: 23, Pages: 3953-3961

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Abstract

Obesity is a public health crisis New methods for amelioration of its consequences are required because it is very unlikely that the social and economic factors driving it will be reversed The pathological accumulation of neutral lipids in the liver hepatic steatosis is an obesityrelated problem whose molecular underpinnings are unknown and whose effective treatment is lacking Here I review how zebrafish a powerful model organism longused for studying vertebrate developmental programs is being harnessed to uncover new factors that contribute to normal liver lipid handling Attention is given to dietary models and individual mutants I speculate on the possible roles of nonhepatocyte residents of the liver the adipose tissue and gut microbiome on the development of hepatic steatosis The highlighted work and future directions may lead to fresh insights into the pathogenesis and treatment of excess liver lipid statesThe postWorld War II rise in obesity continues unabated 1 and it is clear that unanticipated and previously unrecognized players in regulating energy homeostasis must be discovered in order to combat the illnesses that follow from calorie excess Indeed the current pharmacologic armamentarium used in treating obesity’s attendant illnesses eg type 2 diabetes mellitus hypertension dyslipidemia atherosclerotic vascular disease has seen some of its gains negated by increased adiposity 2 Thus there is pressing need for systematic and comprehensive strategies for identifying novel genes that participate in all aspects of energy homeostasisSpecial attention is needed for phenotypes of excessive and ectopic lipid accumulation because of the poorly understood reasons driving their development and the toxic effects of ectopic lipid accumulation on the whole organism More concretely multiple lines of evidence indicate adipose tissue has a finite capacity to safely store neutral lipids The spillover of lipid metabolites from overstuffed adipocytes into the circulation leads to a host of problems including insulin resistance hepatic steatosis intramyocellular liposis accelerated atherosclerosis hypertension and βcell dysfunction 3 While metabolic syndrome and type 2 diabetes mellitus are the most prominent manifestations of deranged lipid storage it has become widely recognized that obesity compounds or causes several other conditions including highoutput heart failure restrictive lung disease certain cancers degenerative joint disease and chronic kidney disease 4Of the obesityrelated disease processes just mentioned it is important to underscore that excessive liver accumulation of lipids hepatic steatosis is present in a large fraction of obese persons 5 Alarmingly hepatic steatosis is found in 30  of the general population is present in nearly twothirds of patients with diabetes mellitus and is seen in over 90  of very obese persons seeking weightreduction surgery 6 Comprehensive reviews cataloging what has been learned from human genomewide association studies on hepatic steatosis 7 8 and from monoallelic human disorders marked by hepatic steatosis 8 leave us with a frustrating picture of the genetic underpinnings of the inappropriate accumulation of liver fat First the frequency of Mendelian inheritance of hepatic steatosis is very low and affected persons often have striking additional phenotypes not found in the general population Similarly in large prospectively gathered cohorts of otherwise seemingly healthy adults only one repeatedly reproduced robust association with a coding polymorphism I148M in a lipidmodifying enzyme gene PNPLA3 has been identified 9 10 Targeted deletion of the Pnpla3 gene in mice does not cause hepatic steatosis 11 12 suggesting that the human polymorphism does not cause a loss of function In support of a dominant or gainoffunction effect of the PNPLA3I148M mutation overexpression of the mutated human PNPLA3 but not wildtype PNPLA3 causes increased mouse liver lipid accumulation 13 This gainoffunction observation reconciles an early report that PNPLA3I148M has only modestly decreased triacylglycerol hydrolase activity 9 initially attributed to prevention of triacylglycerol breakdown with more recent work showing that PNPLA3I148M has increased lysophosphatidic acid acetyltransferase activity relative to wildtype PNPLA3 and is thereby a major enzyme of triacylglycerol synthesis that has only modest triacylglycerol hydrolase activity 14Other associations between human polymorphisms and hepatic steatosis have smaller attributable risk or are not reproducible in more diverse cohorts 15 16 leaving us with a frustratingly incomplete picture of which genes might contribute to this complex phenotype This frustration mirrors the clinical heterogeneity of the disorder being studied and the lack of effective treatments for it Hepatic steatosis is the first step in a spectrum of disorders that encompasses inflammation steatohepatitis fibrosis cirrhosis and cancer hepatocellular carcinoma 17 These interrelated conditions are collectively referred to as nonalcoholic fatty liver disease NAFLD There are limited therapeutic options for permanently ameliorating hepatic steatosis 18 19 and there are no methods for reversing hepatic fibrosis or preventing hepatocellular carcinoma due to NAFLD 20 Indeed the highestquality clinical trial shows very modest benefits for taking pioglitazone an insulinsensitizing Peroxisome proliferator activated receptor gamma agonist with multiple longterm safety concerns 19 Paralleling this disappointing result are the genomewide association observations that while many persons with NAFLD are obese and even have diabetes genes directly involved in insulin signaling have not been implicated in the pathogenesis of this condition 7 8 Thus very high direct and indirect health costs are sustained by inappropriate accumulation of neutral lipids in the liver and little by way of pharmacologic agents is available to reverse thisUltimately the inability to treat NAFLD reflects a lack of detailed knowledge of what triggers it 7 and what drives its progression The first step of NAFLD is the inappropriate accumulation of triacylglycerol in the hepatocyte 21 This accumulation may be due to excessive de novo hepatic lipid production decreased hepatic secretion of very low density lipoprotein particles diminished βoxidation of fatty acids in the liver more subtle defects in regulating energy homeostasis including insulin resistance or central nervous system nutrient sensing a combination of these factors or some yettobeappreciated mechanisms Since each of these possibilities could be amenable to therapeutic exploitation understanding their regulation is paramountAnatomy of late larval zebrafish Within the first week of life zebrafish larvae have functional circulatory and digestive systems The latter is under neuroendocrine control as represented by function pancreatic islets of Langerhans which synthesis insulin and glucagon After 5–7 days of feeding beginning 5 dpf they accumulate lipids in the visceral adipose depot At this age the animal remains sufficiently transparent to allow for wholemount imaging of internal organs

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