World J Gastroenterol 2012 March 21; 18(11): 1141-1153 ISSN 1007-9327 (print) ISSN 2219-2840 (online) 2012 Baishideng. All rights reserved.
EDITORIAL Genetically modified mouse models for the study of
nonalcoholic fatty liver disease

Perumal Nagarajan, M Jerald Mahesh Kumar, Ramasamy Venkatesan, Subeer S Majundar, Ramesh C Juyal Perumal Nagarajan, Subeer S Majundar, Ramesh C Juyal, the treatment of NAFL��� Ideal animal models for NASH Small Animal Facility, National Institute of Immunology, New should closely resemble the pathological characteristics Delhi 110067, India observed in humans�� To date, no single animal model M Jerald Mahesh Kumar, Animal House, Centre for Cellular has encompassed the full spectrum of human disease and Molecular Biology, Hyderabad 500007, India progression, but they can imitate particular character- Ramasamy Venkatesan, Animal House, JNU, New Delhi istics of human disease�� Therefore, it is important that Author contributions: Nagarajan P drafted and wrote the ar- the researchers choose the appropriate animal model�� ticle; Mahesh Kumar MJ and Venkatesan R collected literature This review discusses various genetically modified ani- and references; Nagarajan P, Majumdar SS and Juyal RC re- mal models developed and used in research on NAFL��� vised the manuscript critically.
Correspondence to: �r � �� Perumal Perumal Nagarajan, 2012 Baishideng�� Al rights reserved�� Facility, National Institute of Immunology, New Delhi 110067, India. naga73@yahoo.com Key words: Nonalcoholic fatty liver disease; Steatosis;
Telephone: +91-11-26703709 Fax: +91-11-26742125 Steatohepatitis; Knockout; Animal models Received: July 6, 2011 Revised: September 19, 2011 Accepted: October 28, 2011 Peer reviewer: Po-Shiuan Hsieh, MD, PhD, Department of
Published online: March 21, 2012 Physiology and Biophysics, National Defense Medical Center, Taipei 114, Taiwan, China Nagarajan P, Mahesh Kumar MJ, Venkatesan R, Majundar SS, Juyal RC. Genetically modified mouse models for the study of nonalcoholic fatty liver disease. World J Gastroenterol 2012; Nonalcoholic fatty liver disease (NAFL�) is associated 18(11): 1141-1153 Available from: URL: http://www.wjgnet.
with obesity, insulin resistance, and type 2 diabetes�� NAFL� represents a large spectrum of diseases rang- ing from (1) fatty liver (hepatic steatosis); (2) steatosis with inflammation and necrosis; to (3) cirrhosis. The animal models to study NAFL�/nonalcoholic steato- hepatitis (NASH) are extremely useful, as there are still many events to be elucidated in the pathology of NASH�� The study of the established animal models has Nonalcoholic fatty liver disease (NAFLD) represents provided many clues in the pathogenesis of steatosis a histological spectrum of liver disease associated with and steatohepatitis, but these remain incompletely un- obesity, diabetes and insulin resistance that extends from derstood. The different mouse models can be classified in two large groups. The first one includes genetically isolated steatosis to steatohepatitis and cirrhosis. Besides modified (transgenic or knockout) mice that sponta- being a potential cause of progressive liver disease, ste- neously develop liver disease, and the second one atosis has been shown to be an important cofactor in the includes mice that acquire the disease after dietary or pathogenesis of many other liver diseases. Mouse models pharmacological manipulation�� Although the molecu- have been developed and the different mouse models can lar mechanism leading to the development of hepatic be classified in two major groups. The first one includes steatosis in the pathogenesis of NAFL� is complex, genetically modified (transgenic or knockout) mice that genetically modified animal models may be a key for spontaneously develop liver disease, and the second one WJG www.wjgnet.com
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Nagarajan P et al �� Genetic mouse models for NAFL� includes mice that acquire the disease after dietary or patic steatosis. These mice readily develop symptoms of pharmacological manipulation. NAFLD and nonalco- NASH upon induction with a second hit, such as feeding holic steatohepatitis (NASH) are increasing due to the with an MCD diet[8]. These mice have normal or elevated prevalence of the metabolic syndrome linked to visceral levels of leptin but are resistant to its effects. Studies have adiposity, insulin resistance, dyslipidemia and type two shown that the db gene encodes the leptin receptor (OB-R) diabetes. In this context, research has been undertaken which is structural y similar to a class I cytokine recep- using animals models for human steatosis and NAFLD tor[9,10]. There are two isoforms; the short OB-Ra isoform to NASH disease progression. Most of the animal has not been shown to have any signaling activity. In models develop a fatty liver and many develop aspects contrast, the OB-Rb isoform has a long intracytoplasmic of steatohepatitis. However, spontaneous development region that contains signal transduction motifs which ac- of fibrosis is very rare. Because it is highly unlikely that tivate the JAK/STAT protein kinase signal transduction NAFLD in the human population is monogenic, study cascade[11]. db/db mice carry a sequence insertion at the of animals with deletion or over-expression of a single 3' end of the mRNA transcript exactly where the OB-Ra gene may not mimic etiology of the human disease at and OB-Rb transcripts diverge. This insertion contains the molecular level. Likewise, choice of experimental diet a stop codon that leads to the premature termination of may not mimic the human diets associated with develop- the OB-Rb long intracel ular signaling domain, loss of ment of NAFLD in man. Although rodent models of function and consequently leptin resistance[12].
hepatic steatosis and/or insulin resistance do not always perfectly reproduce the human pathology of NAFLD, Yellow-obese agouti (Ay) mice
the use of transgenic, knockout, and knockdown mouse KK-Ay mice are a cross-strain of diabetic KK mice[13] models have helped over the past years to better our un- and lethal yel ow (Ay) mice, which carry mutation of the derstanding of the molecular determinants of NAFLD. agouti(a) gene on mouse chromosome 2[14]. KK-Ay mice This literature review describes different genetically develop maturity-onset obesity, dyslipidemia, and insulin modified mouse models that exhibit histological evidence resistance, in part because of the antagonism of melano- of hepatic steatosis or, more variably, steatohepatitis. cortin receptor-4 by ectopic expression of the agouti pro- tein[14]. Importantly, these mice present hyperleptinemia GENETIC MODELS FOR NAFLD
and leptin resistance without defects in the ObR gene, and the expression of adiponectin is conversely down- regulated[15,16]. The phenotype of KK-Ay mice, including The ob/ob mice carry a spontaneous mutation in the altered adipokine expression, quite resembles metabolic leptin gene (leptin-deficient). These mice are hyperpha- syndrome in humans indicating the potential useful- gic, inactive, extremely obese and are severely diabetic, ness of this strain as a model of metabolic syndrome with marked hyperinsulinemia and hyperglycemia. ob/ob NASH[17,18]. In fact, KK-Ay mice are more susceptible to mice develop NASH spontaneously[1], but unlike human experimental steatohepatitis induced by MCD diet.
NAFLD, ob/ob mice do not spontaneously progress from steatosis to steatohepatitis. ob/ob mice require a ‘second hit' to be administered in order to trigger progression A valuable model for the study of the effects of altera- to steatohepatitis. This may be provided by exposure to tion in fatty acid (FA) utilization on insulin responsive- small doses of lipopolysaccharide (LPS) endotoxin, etha- ness is the recently generated CD36-deficient mouse[19,20]. nol exposure or hepatic ischemia-reperfusion chal enge CD36, also known as fatty acid translocase (FAT)[21], is a which all provoke a severe steatohepatitis and frequently multispecific, integral membrane glycoprotein[22,23] that has acute mortality[2-5]. ob/ob mice require other stimuli such been identified as a facilitator of FA uptake. Its function as a methionine choline deficient (MCD) diet or a high in binding and transport of FA was documented in vitro fat diet to trigger progression to steatohepatitis. The ef- by affinity labeling with FA derivatives and by cell trans- fects of leptin deficiency on several aspects of physiol- fection studies[23,24]. The CD36-deficient mouse exhibits ogy increase the complexity of studies while using this greater than 60% decrease of FA uptake and utilization strain[6]. Similarly, the limited fibrotic capacity of a leptin- by heart, skeletal muscle, and adipose tissues and thereby deficient model means that it is best suited to studies increases FA delivery to liver and exhibits increased plas- investigating the mechanisms behind the development ma free fatty acid (FFA) and triglyceride (TG) levels[20]. of steatosis and the transition to steatohepatitis. Recent The pathogenic role of FAT/CD36 in hepatic steatosis work demonstrates that the apparent flaws in this model in rodents is well-defined[25].
can be turned to advantage, providing new insights into stellate cell function and the progression to fibrosis.
regulatory-element binding protein 1a-mice
Sterol regulatory-element binding protein (SREBP) family The db/db mice have a natural mutation in the leptin re- members have been established as transcription factors ceptor (Ob-Rb) gene[7]. These mice are obese with insulin regulating the transcription of genes involved in cholester- resistance, and are able to develop macrovesicular he- ol and FA synthesis. In vivo studies have demonstrated that WJG www.wjgnet.com
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Nagarajan P et al �� Genetic mouse models for NAFL� SREBP-1 plays a crucial role in the dietary regulation of of leptin[36] or by transplanting normal adipose tissue[37]. most hepatic lipogenic genes[26,27]. Physiological changes By contrast, transplantation of adipose tissue from ob/ob of SREBP-1 protein in normal mice by dietary manipula- mice did not reverse the phenotype of the A-ZIP/F-1 tion such as placement on high carbohydrate diets, poly- mice indicating that leptin deficiency strongly contrib- unsaturated FA-enriched diets, and fasting-refeeding regi- utes to the metabolic complications in lipodystrophy[38].
mens has been reported[28,29]. SREBP-1a transgenic mice, under the control of liver specific Phosphoenolpyruvate Peroxisome proliferator-activated receptor alpha-/- mice
carboxykinase promoter (TgSREBP-1a), show a massively Peroxisome proliferator-activated receptor alpha (PPARα) enlarged liver and atrophic peripheral white adipose tissue, is expressed in the liver and other metabolical y active tis- and develop steatosis[30].
sues including striated muscle, kidney and pancreas[39,40]. Many of the genes encoding enzymes involved in the mi- tochondrial and peroxisomal FA beta-oxidation pathways Leptin has similar effects in lipodystrophic rodents, most are regulated by PPARα. In wild-type mice, peroxisome notably in aP2-nSREBP-1c transgenic mice. These ani- proliferators are compounds that induce lipid catabolism mals express a truncated, constitutively active form of and an associated intracel ular increase in peroxisome the SREBP-1c transcription factor under the control of number and enzymatic activity. PPARα mutated mice the adipose tissue specific aP2 promoter and develop exhibit alterations of intracel ular lipid processing, par- lipodystrophy with very low plasma leptin levels. These ticularly in response to peroxisome proliferators. Mice mice are also hyperphagic and have massive fat accumula- deficient in PPARα exhibit severe hepatic steatosis when tion in peripheral tissues with hyperglycemia and hyper- subjected to fasting for 24-72 h, indicating that a defect insulinemia[31,32]. This mouse model has markedly reduced in PPARα-inducible FA oxidation accounts for severe body fat and develops liver steatosis, profound insulin FA overload in liver, causing steatosis, in contrast to the resistance, and increased levels of triglycerides[31,32].
aP2-diptheria toxin mice
Galactin-3 knockout mice
The aP2/DTA mice have low serum leptin levels and are Galectin-3, a beta-galactoside-binding animal lectin, is hyperphagic. These mice when fed a control diet are hy- a multifunctional protein. Galectin-3 plays a role in the perlipidemic, hyperglycemic, and have hyperinsulinemia regulation of hepatic stellate cell (HSC) activation in vitro indicative of insulin-resistant diabetes. These mice are and in vivo, thereby identifying galectin-3 as a potential born normally and initially lack any distinguishing phe- therapeutic target in the treatment of liver fibrosis. This notypic features, but develop atrophy and necrosis of model plays a role in investigating liver carcinogenesis the adipose tissue at five to six months resulting in the based on a natural history of NAFLD[43]. Previous complete absence of subcutaneous or intra-abdominal studies have also suggested that galectin-3 may play an adipose tissue at eight to nine months of age[33]. This late important role in inflammatory responses. The livers onset of adipose tissue loss is associated with reduced of gal3(-/-) male mice at six months of age displayed leptin levels, increased food consumption, hyperlipid- mild to severe fatty change. The liver weight per body emia, hyperglycemia and insulin resistance. Monosodium weight ratio, serum alanine aminotransferase levels, liver glutamate-treated aP2/DTA mice develop gross hepato- triglyceride levels, and liver lipid peroxide in gal3(-/-) megaly as a result of severe fatty changes in the liver[33].
mice were significantly increased compared with those in gal3(+/+) mice. Furthermore, the hepatic protein levels of advanced glycation end-products (AGE), receptor for The A-ZIP/F-1 mice express a dominant negative ver- AGE, and PPARγ were increased in gal3(-/-) mice rela- sion of the C/EBPα leucine zipper domain that po- tive to gal3(+/+) mice[43,44].
tently interferes with adipocyte differentiation[34]. The A-ZIP/F-1 mouse (A-ZIPTg/+) is a model of severe Acetyl CoA oxidase-/- mice
lipoatrophic diabetes and is insulin resistant, hypolepti- Acyl-coenzyme A oxidase (AOX) is the rate-limiting nemic, hyperphagic, and shows severe hepatic steatosis. enzyme in peroxisomal FA β-oxidation for the prefer- This mouse has essential y no white adipose tissue, re- ential metabolism of very long-chain FAs. AOX null duced brown fat and severe metabolic phenotype with (AOX-/-) mice have defective peroxisomal β-oxidation a reduced life span. These mice display massive hepa- and exhibit steatohepatitis. Microvesicular fatty change tomegaly causing increased body weight, liver steatosis, in hepatocytes is evident at 7 d. At 2 mo of age, liv- severe diabetes (hyperglycemia, hyperinsulinemia, hyper- ers show extensive steatosis and they have clusters of phagic, polydipsia and polyuria), and are hypertensive[35]. hepatocytes at periportal areas with abundant granular They have increased triglycerides and FFA levels, alveolar eosinophilic cytoplasm rich in peroxisomes. At 4-5 mo foam cells and reduced leptin levels. These mice are un- there is increased PPARα, cytochrome P450, Cyp 4a10, able to sustain glucose levels during fasting. The insulin and Cyp4a14 expression. By 6 to 7 mo, however, there is resistance and much of the liver steatosis in the A-ZIP/ a compensatory increase in FA oxidation and reversal of F-1 mice can be reversed by transgenic over-expression hepatic steatosis resulting from hepatocellular regenera- WJG www.wjgnet.com
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Nagarajan P et al �� Genetic mouse models for NAFL� tion[45,46]. The AOX-/- mice proceed to develop adeno- strain may be useful in studies of fatty liver and insulin mas and carcinomas by 15 mo of age[46,47].
signaling. Piguet et al[61] have investigated the effects of hypoxia in the PTEN-deficient mouse, a mouse model Aromatase (CYP 19)-deficient mice
that develops NAFLD. The authors also showed that a Aromatase P450 (CYP19) is an enzyme catalysing the short period (7 d) of exposure to hypoxia aggravates the conversion of androgens into estrogens[48]. These mod- NAFLD phenotype, causing changes in the liver that are els present dyslipidemia, central obesity, hypercholester- in keeping with NASH, with increased lipogenesis and olemia, hyperinsulinemia, hyperleptinemia, and hypertri- glyceridemia[49], and importantly the male mice have he- patic steatosis. Aromatase knockout (ArKO) mice have a Methionine adenosyl transferase 1A -/- mice
similar phenotype to that of estrogen receptor null mice Mice deficient in methionine adenosyl transferase 1A (the with increased gonadal fat pad weight[50]. Only ArKO enzyme responsible for SAM synthesis in the adult liver) males have elevated hepatic triglyceride levels leading to have a decrease in hepatic SAM levels and spontaneously hepatic steatosis partly due to an increase in expression develop steatosis, NASH, and hepatocel ular carcinoma of enzymes involved in de novo lipogenesis and transport- (HCC)[62]. By three months of age, these mice have hepa- ers involved in FA uptake[51-53].
tomegaly with macrovesicular steatosis. These mice also have increased mRNA levels of CYP2E1 and UCP2, and levels of glutathione. Also, these mice have changes in the Mitochondrial β-oxidation of FAs is the major source expression of genes involved in cel proliferation of lipid of energy for skeletal muscle and the heart, and it plays and carbohydrate metabolism[63]. These mice are predis- an essential role in intermediary metabolism in the liver posed to liver injury and have impaired liver regeneration and impairment of mitochondrial β-oxidation in patho- after partial hepatectomy[64].
genesis of NAFLD. The fetuses of Mtpa-/- mice ac- cumulate long chain FA metabolites and have low birth Adiponectin null mice
weight compared with the Mtpa+/- and Mtpa+/+ litter- Adiponectin is an adipokine abundantly produced from mates. Mtpa-/- mice suffer neonatal hypoglycemia and adipocytes[65,66]. Adiponectin is an anti-inflammatory sudden death 6-36 h after birth. Analysis of the histo- adipocyte-derived plasma protein known to al eviate ste- pathological changes in the Mtpa-/- pups revealed rapid atosis and inflammation in NAFLD[65-67]. Two adiponectin development of hepatic steatosis after birth and, later, receptors (adipoR1 and adipoR2) have been identified significant necrosis and acute degeneration of the car- and found to be expressed in various tissues[68]. AdipoR1 diac and diaphragmatic myocytes. However, studies by is abundantly expressed in skeletal muscles, whereas adi- Ibdah et al[54] indicated that aged but not young MTPa+/- poR2 is present predominantly in the liver, suggesting a mice developed hepatic steatosis with elevated alanine role of adipoR2 in hepatic adiponectin signaling[68,69]. The aminotransferase (ALT), basal hyperinsulinemia, and physiological roles of adipoR1 and adipoR2 have recently increased insulin compared with MTPa+/+ littermates. been investigated by several laboratories in adipoR1/2 Significant hepatic steatosis and insulin resistance devel- knockout mice. Both adipoR1 and adipoR2 knockout mice oped concomitantly in the MTPa+/- mice at 9-10 mo of exhibit mild insulin resistance[70]. In adipoR1/R2 double age. The cause resides in heterozygosity for β-oxidation knockout mice the binding and actions of adiponectin are defects that predisposes to NAFLD and insulin resis- abolished, resulting in increased tissue triglyceride content, tance in aging mice[55]. inflammation oxidative stress[70-73] and mice exhibit im- paired liver regeneration and increased hepatic steatosis.
Phosphatase and tensin homologue -/- mice
Phosphatase and tensin homologue (PTEN) is a mul- Bid null mice
tifunctional phosphatase whose substrate is phosphati- The protein Bid is a participant in the pathway that leads dylinositol-3,4,5-triphosphate and which acts as a tumor to cell death (apoptosis), mediating the release of cyto- suppressor gene that downregulates phosphatidyl ino- chrome from mitochondria in response to signals from sitol kinases[56,57]. Hepatocyte-specific PTEN-deficient "death" receptors known as tumor necrosis factor (TNF) mice spontaneously develop steatosis, steatohepatitis, receptor 1/Fas on the cell surface. Genetic inactivation and hepatocel ular carcinoma[58,59]. By 10 wk of age, these of Bid, a key pro-apoptotic molecule that serves as a link mice have increased concentrations of triglyceride and between these two cell death pathways, significantly re- cholesterol esters, and a histological analysis displays mi- duced caspase activation, adipocyte apoptosis, prevented cro- and macrovesicular lipid vacuoles. At 40 wk of age, adipose tissue macrophage infiltration, and protected they have macrovesicular steatosis, mal ory bodies, bal- against the development of systemic insulin resistance looning degeneration, and sinusoidal fibrosis[59-60]. Mice and hepatic steatosis independent of body weight[74,75]. that are homozygous for this al ele are viable, fertile, These mice can be used in research based on adipocyte and normal in size and do not display any gross physical apoptosis which is a key initial event that contributes to or behavioral abnormalities. When crossed to a strain macrophage infiltration into adipose tissue, insulin resis- expressing Cre recombinase in liver, this mutant mouse tance, and hepatic steatosis associated with obesity.
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Nagarajan P et al �� Genetic mouse models for NAFL� Fas adipocyte-specific (AfasKO) null mice
flanked Nemo[87] or Ikk2[88] al eles with Alfp-cre transgenic Fas (CD95), a member of the TNF receptor super fam- mice that mediate efficient Cre recombination in liver ily, is a major contributor to apoptosis in many cel s. parenchymal cel s, including hepatocytes and biliary epi- Fas activation may contribute to obesity-induced insulin thelial cel s, but not in endothelial or Kupffer cel s[89]. resistance, since mice lacking Fas in adipocytes were NEMOLPC-KO mice were born and reached weaning age at partly protected from developing insulin resistance. In the expected Mendelian frequency[90]. These mice showed particular, Fas activation led to increased release of pro- efficient ablation of the respective proteins in whole-liver inflammatory cytokines, and reduced insulin-stimulated extracts and NF-κB activity in the liver was completely glucose uptake in 3T3-L1 adipocytes[75]. Fas-deficient abolished[91,92]. Hepatocytes are LPS sensitive. When fed a (Fas-def) mice show increased insulin-stimulated glucose high-fat diet, mice had reduced β-oxidation and upregu- incorporation when compared to wild type (WT) with lated PPAR-γ, SReBP1 and FA synthase causing increased higher expression levels of Akt[76,77].
de novo lipid synthesis and macrovesicular steatosis with increased HCC occurrence[91,92].
Interleukin-6 KO mice
Interleukin-6 (IL-6) is an adipocytokine associated with Jun N-terminal kinase 1 null mice
NALFD and obesity that is secreted in larger amounts Jun N-terminal kinase (JNK) 1 null mice have less he- by visceral fat compared to subcutaneous fat in obese patic inflammation and fibrosis when fed a choline- adults[78]. Increased systemic IL-6 is associated with in- deficient, l-amino acid-defined (CDAA) diet due to the creased inflammation and fibrosis in NAFLD patients[79]. absence of JNK1 in immune cells. As JNK is activated Expression of IL-6, a major proinflammatory cytokine, by oxidants and cytokines and regulates hepatocel ular is increased in animal models of NAFLD. Hepatic IL-6 injury and insulin resistance, this kinase may mediate production may also play an important role in NASH the development of steatohepatitis. JNK promotes the development, as well as in systemic insulin resistance development of steatohepatitis as MCD diet-fed JNK and diabetes. IL-6 is elevated in the plasma and periph- null mice have significantly reduced levels of hepatic tri- eral blood monocytes of patients with fatty diseases, glyceride accumulation, inflammation, lipid peroxidation, including alcoholic liver disease and non-alcoholic ste- liver injury, and apoptosis compared with wild-type and atohepatitis, and elevation of IL-6 correlates with the JNK2 -/- mice[93,94]. Hence JNK1 is responsible for JNK progression and severity of liver disease, suggesting that activation that promotes the development of steato- IL-6 may be involved in the pathogenesis of fatty liver hepatitis in the MCD diet model[93]. JNK1 KO produces disease[80,81]. Studies using Il6-/- mice show these animals lean, male JNK1 KO mice which have decreased body display obesity, hepatosteatosis, liver inflammation and weights, fasting blood glucose levels, and fasting blood insulin resistance when compared with control mice on insulin levels compared to their wild‐type controls[94]. a standard chow diet[82]. This model can be used to study a combination of ge- netic and dietary chal enges that constitute the disease TNF alpha KO mice
etiology for NASH development and mimic more close- TNF-α appears to play a central role in the development ly the pathogenesis of human NAFLD/NASH.
of hepatic steatosis. TNF-α, by mechanisms not com- pletely defined, is over expressed in the liver of obese Toll-like receptor 9 KO mice
mice and is an important mediator of insulin resistance Development of NASH involves the innate immune in both diet-induced and ob/ob models of obesity[83,84]. system and is mediated by Kupffer cells and HSCs. Toll- Data from animal and clinical studies indicate that like receptor 9 (TLR9) is a pattern recognition receptor TNF-α mediates not only the early stages of fatty liver that recognizes bacteria-derived cytosine phosphate disease but also the transition to more advanced stages guanine-containing DNA and activates innate immunity. of liver damage[85,86]. Mice homozygous for the TNF tar- Mice deficient in TLR9 have reduced steatohepatitis geted mutation are viable and fertile. Further, male mu- and fibrosis[95]. Hence this model can be used to study tant mice at 28 wk old display lower insulin, triglyceride, NAFLD involving innate immunity.
and leptin levels compared to wild type controls.
LDLR KO and farnesoid X receptor KO mice
Farnesoid X receptor (FXR) is essential for regulating The IκB kinase (IKK) subunit NEMO/IKKγ is essential bile-acid synthesis and transport. Mice with FXR defi- for activation of the transcription factor nuclear factor ciency have severe impairment of bile-acid homeostasis kappa B (NF-κB), which regulates cel ular responses to and manifest systemic abnormalities including altered inflammation. NEMO-mediated NF-κB activation in lipid and cholesterol metabolism features known to be hepatocytes has an essential physiological function to pre- associated with the metabolic syndrome and NASH. vent the spontaneous development of steatohepatitis and Kong et al[96] studied LDL receptor knockout (LDLr-/-) hepatocel ular carcinoma. These mice were generated with mice fed with a high-fat diet for 5 mo, and checked liver parenchymal cel -specific knockout of these subunits whether FXR deficiency contributed to NASH develop- (NEMOLPC-KO, IKK2LPC-KO) by crossing mice carrying loxP- ment. Both high-fat diet and FXR deficiency increased WJG www.wjgnet.com
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Nagarajan P et al �� Genetic mouse models for NAFL� serum ALT activity, whereas only FXR deficiency in- is a 130-kDa transmembrane glycoprotein expressed creased bile-acid and ALP levels. FXR deficiency and on blood and vascular cells. Goel et al[104] demonstrated high-fat feeding increased serum cholesterol and tri- that genetic deficiency of PECAM-1 potentiates the glycerides. Although high-fat diet led to macrosteatosis development and progression of NASH. After 3 wk on and hepatocyte bal ooning in livers of mice regardless an atherogenic diet, these mice developed mild microve- of genotype, no inflammatory infiltrate was observed sicular steatosis predominantly in hepatic parenchymal in the livers of LDLr-/- mice. In contrast, in the livers cells in the centrilobular region. At 9 and 18 wk on the of LDLr-/-/FXR-/- mice, foci of inflammatory cel s atherogenic diet, more severe steatosis with lobular and were observed when they were fed with control diet sinusoidal inflammation developed in the livers, which and were greatly increased when fed with the high-fat are consistent with the typical histological features of diet[96,97]. This model can be used to study a combination of genetic and dietary challenges that constitute the dis- ease etiology for NASH development and mimic more ApolipoproteinB 38.9 mutant mice
closely the pathogenesis of human NAFLD/NASH.
Fatty liver is prevalent in apolipoproteinB (apoB)-defec- tive familial hypobetalipoproteinemia (FHBL). Similar Myd88 KO mice
to humans, mouse models of FHBL produced by gene Chemokines, strongly induced by TLR stimulation, play targeting (apoB+/38.9) manifest low plasma cholesterol an important role in the development of metabolic syn- and increased hepatic TG even on a chow diet due to drome including NAFLD. TLR4- and MyD88-deficient impaired hepatic VLDL-TG secretive capacity. These mice, which are resistant to metabolic syndrome, show mice will be useful to study the genetic and molecular reduced chemokine production compared with WT mechanism of apoB defects and lipid metabolism/liver mice[98,99]. MyD88 is a key molecule in the development fat accumulation, the relationship between hepatic ste- of metabolic syndrome including NAFLD[98,99]. MyD88, atosis and insulin resistance, and the progression of ad- an adaptor protein for all TLRs except for TLR3, is vanced NAFLD and atherosclerosis[105].
required for the expression of various inflammatory cytokines and chemokines[100]. MyD88-deficient mice are protected from metabolic syndrome as well as ath- Cystathionine-synthase (CBS) deficiency causes severe erosclerosis[98,99] and from liver injury induced by bile hyperhomocysteinemia, which confers diverse clini- duct ligation or carbon tetrachloride[101,102]. Miura et al[100] cal manifestations, notably liver disease. Robert et al[106] demonstrated that MyD88-deficient mice on a CDAA reported that CBS-deficient mice showed inflamma- diet show less steatohepatitis with less insulin resistance tion, fibrosis, and hepatic steatosis. These mice also had compared with wild type mice. Inflammatory cytokines pathological resemblance to steatohepatitis and a pattern and fibrogenic factors are also significantly suppressed of perivenous and pericel ular hepatic fibrosis around in MyD88-deficient mice compared with wild type mice lipid-laden hepatocytes. CBS KO mice develop hepatic fed a CDAA diet[100].
steatosis more tardily than inflammation and fibrosis at 8-32 wk old.
Fatty liver dystrophy knockout mice
In addition to the above KO animals, Postic et al[107] Fatty liver dystrophy (fld) is a spontaneous point mutation has demonstrated a few animal models modulating en- in Lpin1 which occurred on C3H/HeJ in 1994. An unsta- zymes in FA synthesis.
ble gait and tremor at 3 wk of age was initial y observed in these mice. The pups from these mice have a fatty liver before reaching weaning age. Mice carrying mutations in Acetyl-CoA carboxylase (ACC) catalyzes the synthesis of the fld gene have features of human lipodystrophy, a ge- malonyl-CoA, the metabolic intermediate between lipo- netical y heterogeneous group of disorders characterized genesis[108] and β-oxidation[109]; this lipogenic enzyme has by loss of body fat, fatty liver, and hypertriglyceridemia garnered significant attention over recent years. In mam- and insulin resistance[103]. Homozygous fld mice have an mals, two ACC isoforms exist, each with distinct tissue dis- enlarged, fatty liver and hypertriglyceridemia that resolve tribution and physiological roles: ACC1 is highly expressed to normal during the weaning transition. However, de- in liver and adipose tissue, whereas ACC2 is predominantly creased overal size, decreased lipid in the fat pads and expressed in heart and skeletal muscle and, to a lesser a peripheral neuropathy persist throughout the lifespan. extent, in liver[110]. It is believed that only ACC1, but not This peripheral neuropathy manifests as a tremor and an ACC2, is committed to de novo lipogenesis in liver. Targeting unsteady gait shortly after 10 d of age and worsens with ACC has beneficial effects on both hepatic steatosis and age. As with the original mutation of fld, homozygous insulin resistance. ACC1-knockout mice (Ac 1-/- mice and females wil breed and raise their litters but homozygous ACC2-/- mice) have been developed to study the effect.
males do not breed.
SCD KO mice
Platelet endothelial cell adhesion molecule-1 null mice
SCD1 has recently become a target of interest for the Platelet endothelial cel adhesion molecule-1 (PECAM-1) reversal of hepatic steatosis and insulin resistance[111]. WJG www.wjgnet.com
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Nagarajan P et al �� Genetic mouse models for NAFL� occurred despite hepatic steatosis and marked obesity Table 1 Potential candidate genes in fatty liver disease
in Elovl6-/- mice[116]. While these results are somewhat Category of genes
surprising given the role of palmitate as a potent inducer Genes affecting insulin resistance ADIPOQ, AKT2, ENPP1, IRS1, of insulin resistance (at least in primary cultures of he- PPARG, HFE, resistin patocytes)[117], they are also interesting since they indicate Genes affecting hepatic lipid synthesis DGAT2, SLC25A13, ACC, that the hepatic FA composition, and particularly the ELOVL6, SCD1, GPAT, SREBP1 conversion of palmitate to stearate, is crucial for insulin Genes affecting hepatic lipid uptake Genes affecting hepatic triglyceride PNPLA2, CGI-58, LIPA sensitivity. It should be noted that the reduced SCD1 expression observed in livers of Elovl6-/- mice could have Genes affecting hepatic lipid export APOB, MTTP, PEMT also contributed to the amelioration of insulin resistance Genes affecting hepatic oxidative GCLC, NOS2, SOD2, HFE, UCP2, in these mice[116].
MAT1A, GST, GSH-Px Genes affecting immune regulation ADIPOQ, ADIPOR1, ADIPOR2, STAT3, TNFα, IL10, IL6, CTLA-4, ChREBP knockdown mice
IL-4, IL-18 ChREBP knockdown led to the expected inhibition of Genes influencing disease progression TGF-β1, 3, PPARα, DDX5, L-PK, ACC, FAS and SCD1 as well as GPAT. While a CPT1A, angiotensin Ⅱ Genes influencing response to CD14, TLR4, NOD2 carbohydrate-response element was previously identified in the promoter region of the GPAT gene[118], its expres- sion was found to be unaffected in the liver of ChREBP- ADIPOQ: Adiponectin; AKT: Beta serine/threonine-protein kinase; knockout mice upon refeeding[119]. It is possible that the ENPP1: Ectonucleotide pyrophosphatase/phosphodiesterase 1; IRS-1: nutritional regulation of GPAT may be more sensitive to Insulin receptor substrate 1; PPARG: Peroxisome proliferator-activated receptor gamma; HFE: Hemochromatosis gene; DGAT2: Diacylglycerol insulin via SREBP-1c than to glucose via ChREBP. Nev- acetyltransferase-2; SLC25A13: Solute carrier family 25 Member 13 (citrin); ertheless, fol owing ChREBP knockdown, a resultant ACC gene: Acetyl-CoA carboxylase alpha; ELOVL6: Elongation of very decrease in lipogenic rates was observed in shChREBP- long chain fatty acids; SCD1 gene: Stearoyl-CoA desaturase gene; GPAT: RNA-treated ob/ob mice, leading to a 50% reduction in Glycerol-3-phosphate acyltransferase; SREBP1: Sterol regulatory element-binding transcription factor 1; APOC3: Apolipoprotein C-Ⅲ; PNPLA2: hepatic and circulating TG concentrations[120]. ChREBP Patatin-like phospholipase domain containing 2; CGI58: Comparative gene knockdown not only affected the rate of de novo lipogen- identification-58; LIPA: Lipase A; APOB: Apolipoprotein B; MTTP: Mi- esis but also had consequences for β-oxidation. There- crosomal triglyceride transfer protein; PEMT: Phosphatidylethanolamine fore, similarly to the liver-specific knockout of SCD1 N-methyltransferase; GCLC: Glutamate-cysteine ligase, catalytic subunit; (LKO mice)[121], the coordinated modulation in FA syn- NOS2: Nitric oxide synthases2; SOD2: Superoxide dismutase-2; UCP2: Uncoupling protein 2; MAT1A: Methionine adenosyltransferaseⅠalpha; thesis and oxidation in liver led to an overall improve- GST: Glutathione S-transferase; ADH: Alcohol dehydrogenase; ALDH: Al- ment of lipid homeostasis in ChREBP-deficient mice. dehyde dehydrogenase; CTGF: Connective tissue growth factor; CTLA-4: The decrease in lipogenic rates observed in LKO mice Cytotoxic T-cell associated antigen-4; GSH-Px: Glutathione peroxidase; was at least partially attributed to a decrease in ChREBP STAT3: Signal transducer and activator of transcription 3; IL: Interleukin; PPAR: Peroxisomal proliferator activated receptor; SCD-1: Stearoyl CoA nuclear protein content[122]. Clearly, ChREBP needs now desaturase-1; TLR: Toll-like receptor; TNFR: TNF-α receptor; DDX5: DEAD to be considered as a key determinant of the molecular box protein 5; CPT1A: Carnitine palmitoyltransferase 1A (liver); NOD2: regulation of the lipogenic pathway.
Nucleotide-binding oligomerization domain containing 2.
SCD1 catalyzes the synthesis of monounsaturated FAs, particularly oleate (C18:1n-9) and palmitoleate (C16:1n-7), MODELS WITH DISRUPTION OF GENES
which are the major components of membrane phos- INVOLVED IN NAFLD
pholipids, TGs, and cholesterol esters. Mice with SCD- 1KO (Scd1-/- mice) show decreased lipogenic gene expres- Table 1 presents a number of candidate genes that are sion and increased β-oxidation and are protected from involved in the pathogenesis of NAFLD and a few are diet-induced obesity and insulin resistance when fed a discussed below.
HC/HF diet[112,113]. Inhibition of SCD1 using an ASO strategy (targeting SCD1 in both liver and adipose tis- Genes affecting lipid metabolism
sues) prevents many of the HF/HC-diet metabolic com- Pemt KO animals: Pemt-/- mice have two selectively
plications, including hepatic steatosis and postprandial disrupted al eles of the Pemt-2 gene at exon 2[123], which encode PEMT, and do not express any PEMT activity in liver. Therefore these mice completely depend on dietary ELOVL6 KO mice
choline intake to meet daily choline requirements. When Elovl6-/- mice are protected against the development fed a diet deficient in choline and insufficient in methio- of hepatic insulin resistance when fed a HF/HC diet, nine, Pemt-/- mice develop decreased PtdCho concentra- despite the accumulation of palmitate concentrations. tions in hepatic membranes, leading to severe liver damage Improvement in insulin signaling (as evidenced by the and death; a choline supplemented diet prevents this[124] restoration in insulin-mediated Akt phosphorylation) and, if provided early enough, can reverse hepatic damage.
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Nagarajan P et al �� Genetic mouse models for NAFL� DGAT2 mice: DGAT2, an isoform of the enzyme ac-
triglyceride concentrations in familial hyperlipidemia[137].
ylCoA: diacylglycerol acyltransferase, catalyses the final stage of triglyceride synthesis in the liver[125]. Overex- Genes affecting oxidative stress
pression of DGAT2 in mice led to a 2.4-fold increase in Glutamate-cysteine ligase: Glutamate-cysteine ligase
hepatic triglyceride content, but no effect on production (GCLC) is the first and rate-limiting enzyme in the synthe- of VLDL triglyceride or apoB[126]. In addition, mice on a sis of glutathione, the major antioxidant in the liver. Liver- high-fat diet that overexpress DGAT develop fatty liver specific deletion of GCLC in mice rapidly leads to hepatic but not glucose or insulin intolerance[127], showing that steatosis and progressive severe parenchymal damage[138].
hepatic steatosis can occur independently of insulin re- sistance. Interestingly, antisense therapy reducing DGAT Nitric oxide synthase: Yoneda et al[139], who studied as-
improves hepatic steatosis, but not insulin sensitivity[128].
sociations of PPARγC1α, also examined the influence of SNPs in the inducible nitric oxide synthase (NOS2) Apolipoprotein C-: Apolipoprotein C-Ⅲ (apoC-Ⅲ)
gene on their NAFLD cohort. iNOS is expressed as part is the most abundant C apolipoprotein in human plasma, of the inflammatory response and in the presence of where it is present as an 8.8-kDa mature protein on chy- superoxide radicals forms peroxynitrite, which can cause lomicrons, VLDL and HDL. ApoC-Ⅲ is synthesized endoplasmic reticulum stress and cell death[140]. iNOS- in the liver and in minor quantities by the intestine[129]. deficient mice develop NASH with high fat diets[141].
Several lines of evidence have implicated apoC-Ⅲ as contributing to the development of hypertriglyceride- Superoxide dismutase-2: Elevated hepatic reactive
mia in the human population. Investigation in apoC3-/- oxygen species play an important role in pathogenesis of mice supports the concept that apoC-Ⅲ is an effective liver diseases, such as alcohol-induced liver injury, hepa- inhibitor of VLDL TG hydrolysis and reveals a potential titis C virus infection, and nonalcoholic steatohepatitis. regulating role for apoC-Ⅲ with respect to the selective Satoshi et al[142] observed significant increases in lipid uptake of cholesteryl esters[130].
peroxidation and TG in the liver of Sod1 KO and double KO mice but not in the liver of Sod2 KO mice. Genes affecting insulin resistance/sensitivity
IRS 1: Studies on mice with targeted disruption of the
Genes affecting immune regulation
Irs genes lend some support to both situations. Irs1 Signal transducer and activator of transcription 3:
knockout (Irs1-/-) mice show significant embryonic and Signal transducer and activator of transcription 3 (STAT3) postnatal growth retardation, suggesting that IRS-1 plays is an acute-phase transcription factor; after hepatic ne- a key role in relaying the growth-stimulating effects of crosis it activates pathways associated with liver regen- insulin and insulin-like growth factor. IRS-1-deficient eration and acute inflammation[143]. STAT3 is also impli- mice also have insulin resistance and mild glucose intol- cated in nutrient metabolism and developing metabolic erance, but do not develop diabetes[131,132].
syndrome. Transgenic mice with hepatic deficiency of STAT3 develop insulin resistance and disturbed glucose Ecto-nucleotide pyrophosphate phosphodiesterase:
homeostasis; whereas the constitutive liver specific ex- Ecto-nucleotide pyrophosphate phosphodiesterase (ENPP1) pression of STAT3 in diabetic mice reduces blood glu- has been shown to negatively modulate insulin receptor cose and plasma insulin concentrations and downregu- and to induce cel ular insulin resistance when over-ex- lates gluconeogenic gene expression[144].
pressed in various cell types. Systemic insulin resistance has also been observed when ENPP1 is over-expressed in multiple tissues of transgenic models and is largely attributed to tissue insulin resistance induced in skel- Inbred strains of mice provide convenient tools to study etal muscle and liver. In the presence of a high fat diet, the pathogenesis of NAFLD because they provide the ENPP1 over-expression in adipocytes induces fatty liver, opportunity to control genetic and environmental fac- hyperlipidemia and dysglycemia, thus recapitulating key tors that might influence the natural history of NAFLD. manifestations of the metabolic syndrome[133].
Various genetic alterations or environmental stressors producing a similar phenotype prove that many differ- Transcription factor 7-like 2: Transcription factor 7-like
ent immunological, neuronal and hormonal factors are 2 (TCF7L2) is a receptor for β-catenin and regulates involved in the pathogenesis of NAFLD[145,146]. Trans- the expression of a multitude of genes involved in cel- genic mouse models also represent gene mediation to lular metabolism and growth. Various studies[134-136] have NAFLD. Therefore, any one of these animal models linked TCF7L2 variation with impaired insulin secretion could be used to clarify how altered cross talk among and risk of diabetes, possibly mediated by altered β-cell immune cells, neurons and endocrine cells promote glucose response. In addition, it regulates adipokine se- NAFLD. In contrast to human genetic studies, animal cretion and triglyceride metabolism through effects on studies have found genes that consistently produce PPAR-γ, CCAAT/enhancer-binding protein, and lipo- disease-like phenotypes, and the underlying genetic ba- protein lipase; TCF7L2 SNPs are associated with serum sis for the phenotypes in these models have often been WJG www.wjgnet.com
March 21, 2012 Volume 18 Issue 11
Nagarajan P et al �� Genetic mouse models for NAFL� elucidated. Animal studies on NAFLD frequently reveal MM, Winkes BM, Barsh GS. Cloning of the mouse agouti significant single-locus effects that can be reproduced gene predicts a secreted protein ubiquitously expressed in across species and/or strains. Such ‘ disease genes'' in mice carrying the lethal yellow mutation. Genes Dev 1993; 7:
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S- Editor Tian L L- Editor Logan S E- Editor Li JY
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I.E.S. "Ramón J. Sender" Apuntes sobre "Textos-Comentario de Texto" TEXTO 1 (Ensayo informativo) El agua de un río está más alta y tiene más energía gravitatoria en el manantial que en la desembocadura. Por eso fluye el agua río abajo hasta el mar. (Si no fuese por la lluvia, todas las aguas continentales fluirían montaña abajo hasta el mar y el nivel del océano subiría ligeramente. La energía gravitatoria total permanecería igual, pero estaría distribuida con mayor uniformidad.)

Microsoft word - heft 15.doc

Vormals NVersZ V Info-Letter ersicherungs- und Haftungsrecht In Zusammenarbeit mit der Neuen Juristischen Wochenschrift Nr. 15 · 14. August 2003 Schriftleiter: Rechtsanwalt Dr. Theo Langheid, Köln Editorial Aktuelles Thema BB – oder: die Macht der Rating - Agenturen RA Dr. Henning Seel: