Skip to main content
NCBI home page
Gene Expression logoLink to Gene Expression
. 2018 Dec 14;19(1):61–67. doi: 10.3727/105221618X15337408678723

Stress of Strains: Inbred Mice in Liver Research

Arlin B Rogers 1
PMCID: PMC6290319  PMID: 30092856

Abstract

Inbred mice are the most popular animals used for in vivo liver research. These mice are genetically defined, readily available, less expensive to maintain than larger animals, and enjoy a broad array of commercial reagents for scientific characterization. C57BL/6 mice are the most commonly used strain. However, other strains discussed, including BALB/c, C3H, A/J, and FVB/N, may be better suited to a particular disease model or line of investigation. Understanding the phenotypes of different inbred mouse strains facilitates informed decision making during experimental design. Model systems influenced by strain-dependent phenotype include tissue regeneration, drug-induced liver injury (DILI; e.g., acetaminophen), fibrosis (e.g., carbon tetrachloride, CCl4), Fas-induced apoptosis, cholestasis, alcohol-induced liver disease and cirrhosis, nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH), and hepatocellular carcinoma (HCC). Thoughtful consideration of the strengths and weaknesses of each inbred strain in a given model system will lead to more robust data and a clearer understanding of translational relevance to human liver disease.

Key words: Liver; Mice, Inbred strains; Genotype; Phenotype; Research; Animal experimentation

INTRODUCTION

Inbred mice are widely used in liver disease research because of their genetic homogeneity, reproducibility of results, inexpensive cost compared with larger species, and availability of a wide array of research reagents for in vivo characterization1. Because the genetic background (genotype) of inbred mouse strains is tightly controlled, physical features and pathophysiologic responses to experimental challenges (phenotype) can be better predicted. The most popular mouse strain is the C57BL/6 (C57-Black, Black-6, B6) strain. Whereas the B6 mouse is characterized by widespread use, detailed phenotypic understanding, and favored status as the background strain for most genetically engineered models, other strains of mice may be more appropriate to address specific questions in liver research. Moreover, as gene editing becomes more common, investigators may be able to insert specific genetic modifications onto any background strain2. This will greatly expand the toolkit of liver researchers by facilitating the study of host–environment interactions across a variety of phenotypic backgrounds. This review introduces a modest sampling of inbred mouse strains commonly used in hepatic research and describes their phenotypes in the context of specific disease models to highlight the importance of strain consideration in any given system. The overall goal is to help reduce investigator stress when selecting strains for liver research.

THE MICE

C57BL/6

A workhorse among mice, the B6 strain is far and away the most widely used in biomedical research. It should be noted that there are multiple substrains of C57BL/6 mice3; the C57BL/6J strain from The Jackson Laboratory is the one most investigators refer to as “B6.” Both biologic and pragmatic factors contributed to the early popularity of this strain. B6 mice are docile and demonstrate reliable breeding kinetics, although they may suffer higher-than-average rates of pup loss under duress. (B6 dams sometimes eat offspring that die spontaneously, leading to an undeserved reputation as infanticidal cannibals4.) Later, with the advent of transgenic technologies, B6 mice proved useful in identifying successful introduction of a genetically engineered mutation because their black fur contrasted with the white 129 mice favored for germ cell gene knockout. Patchy gray coats in the offspring signaled successful chimerism. Over the years, B6 mice became entrenched in the scientific consciousness for the simple fact that so many previous studies had utilized the strain, and there was a body of literature. B6 mice became famous for being famous. Popularity aside, certain disease conditions are ideally suited for study in B6 mice. Because this strain is more willing to ingest ethanol than others, B6 mice are favored for modeling alcoholic liver disease (ALD)5. Slow metabolism leading to diet-induced obesity (DIO), metabolic syndrome, and type 2 diabetes (T2D) facilitates investigation of nonalcoholic fatty liver disease (NAFLD) in this strain6. Viral hepatitis research has been advanced by the use of B6 mice transfected with whole or partial genomes of hepatitis B and C viruses7. Wild-type (WT) B6 mice are more resistant to chemically induced hepatocellular carcinoma (HCC) than strains such as C3H and DBA, making it possible to identify quantitative trait loci (QTL) associated with the disease in genetically defined hybrids8,9. A wide array of genetically engineered mutant mice (GEMM) on the B6 background have provided extensive insights into specific genes and pathways involved in different liver diseases. For these and other reasons, B6 mice are likely to remain the most widely used strain in liver research for years to come.

BALB/c

As ornery as B6 are docile, animal handlers would probably prefer to see the Bagg albino c-strain (BALB/c) decline in popularity. Unfortunately for the caretakers, BALB/c remains a popular strain for numerous types of studies, particularly those where their Th2-polarized immune system serves as a stark contrast to the Th1-centric C57BL/610. Additionally, sensitivity to carbon tetrachloride (CCl4) and other hepatotoxins makes the BALB/c strain a favorite in studies of acute chemical injury and liver fibrosis11. Continued use of BALB/c mice across a range of liver disease models means that the animal facility first aid kit will need to remain well stocked.

C3H

Along with CBA and DBA/2 strains, C3H mice have a high susceptibility to both chemically induced and spontaneous HCC12. Historically, this strain also showed unusually high sensitivity to Gram-negative bacterial infections but resistance to lipopolysaccharide (LPS; endotoxin) toxicity. Subsequently, it was learned that this was due to a spontaneous mutation in toll-like receptor 4 (TLR4)13. The mutation occurred in mice at The Jackson Laboratory (C3H/HeJ) but not at other facilities (C3H/HeN, C3H/HeOuJ) producing a natural model to study TLR4 function14. C3H mice form half of the equation in the generation of B6C3F1 hybrids used in most NTP studies15.

A/J

Small and lean, A/J mice often are used to evaluate genetic resistance to NAFLD in the context of DIO and other metabolic challenges. In this regard, they serve as a metabolic foil to the B6 strain, which is prone to obesity and fatty liver16. To study genetic determinants of these divergent metabolic phenotypes, chromosome-substitution strain or “consomic” mice have been made between B6 and A/J strains, which bear the inbred genome of the parental strain with the exception of a complete chromosome from the donor strain. (In most cases, A/J is the chromosome donor, and B6 is the recipient.) Using this approach, QTL specifying lean versus obese phenotypes have been localized to chromosomes 6 and 1717,18. In addition to metabolic research, A/J mice develop chronic hepatitis and HCC that are histologically indistinguishable from human chronic viral hepatitis when infected with the enterohepatic bacterium Helicobacter hepaticus 1. This remains the only WT mouse model of infectious liver cancer employing a native murine pathogen.

FVB/N

This strain was saved from declining popularity by its large embryos for easy pronuclear injection and permissiveness to embryonic stem cell transfection at the dawn of the GEMM era. To this day, a large number of transgenic mice remain on the FVB/N background (“transgenic” = new gene added, “knockout” = existing gene inactivated). FVB mice are prone to multiple forms of cancer, and carcinomas in particular (tumors of epithelial origin), a stroke of luck for oncology scientists relying on transgenic approaches19. In addition to transgenic modeling, WT FVB/N animals also are employed in certain metabolic and toxicology studies20.

THE MODELS

Liver Regeneration

As the only visceral organ capable of full regeneration following significant loss of functional mass, the liver is the gold standard to model tissue development and maturation. The most widely applied model is two thirds (or ∼70%) partial hepatectomy, although regeneration studies following chemical and other types of injury are also employed21. Whereas different strains of mice have been used in liver regeneration research, surprisingly few studies have directly compared responses between strains. Liver regeneration is delayed in C3H/HeJ mice compared with C3H/HeN, which has been attributed to differences in sinusoidal blood flow; however, this is not driven exclusively by TLR4 because TLR4−/− mice show normal regenerative capacity compared with WT B6 controls22.

Drug-Induced Liver Injury: Acetaminophen

As a primary center of xenobiotic processing and elimination, the liver is highly susceptible to acute toxicity and drug-induced liver injury (DILI). This section highlights acetaminophen (APAP) toxicity as a representative model. Mice given a single high dose of APAP undergo centrilobular necrosis resulting in very high ALT and AST levels within 24 h, similar to human overdose23. Injury is exacerbated if mice are fasted prior to dosing due to depleted levels of reduced glutathione. Whereas early work suggested that outbred Swiss–Webster mice exhibited apoptosis following APAP challenge, subsequent work showed that caspase 3 activation was minor in these mice and that the pathophysiology of the injury was equivalent with C57BL/6 mice in terms of lesions and biomarkers24. Even within the B6 line, there are substrain differences in APAP sensitivity, as C57BL/6N mice show more vulnerability than C57BL/6J3. Mechanisms accounting for these different phenotypes remain to be elucidated.

Fibrosis: Carbon Tetrachloride

Compared with humans and other animal species, mice mount weak fibrotic responses even in the face of severe liver injury. CCl4, once a common compound in dry cleaning and a major cause of morbidity among workers in that industry25, is now primarily employed in mouse research as an inducer of fibrosis. CCl4 is metabolized into toxic intermediates by the cytochrome P450 enzyme CYP2E1, which is concentrated in centrilobular hepatocytes. Central degeneration and/or necrosis may occur at high challenge concentrations. Interestingly, zone 1 (periportal) hepatocytes also undergo coagulative necrosis, and CCl4-induced fibrosis is highly portocentric with frequent portal–portal but rare portal–central bridging26. Hepatocytes undergo a combination of apoptotic and oncotic necrosis, resulting in rapid cell dropout, scarring, and fibrosis. This portal pattern of fibrosis is distinct from that seen in ALD and NAFLD featuring a primarily perivenular/pericellular (“chickenwire”) pattern of collagen deposition27,28. BALB/c mice are most susceptible to CCl4 toxicity, although B6 and C3H mice also may show degenerative and fibrotic changes11. For this reason, investigators studying mechanisms and intervention of liver fibrosis/cirrhosis frequently turn to the CCl4 model in BALB/c mice. Thioacetamide invokes similar changes and is processed in a manner similar to CCl4 29. Bile duct ligation also invokes fibrosis resulting from severe cholestasis (see section on Cholestatic Hepatitis).

Apoptosis

The liver is an especially valuable tissue for the study of apoptosis given the readiness of programmed cell loss and replacement in this compartment. Fas ligand (CD95) binding to the Fas receptor, which is expressed at moderate to high levels in up to 25% of hepatocytes, results in activation of the canonical Fas-associated death domain30. This is a generalized model for extrinsic programmed cell death that may occur via other pathways including TNFRSF1A associated via death domain31. C3H mice have a higher susceptibility to Fas-induced apoptosis than C57BL/6 and FVB/N mice, a finding attributed to increased levels of caspase and proapoptotic mitochondrial inner membrane proteins in the former32.

Cholestatic Hepatitis

Bile salts are proinflammatory when encountered outside of their appropriate niche. Cholestasis is associated with hepatitis in humans and in mouse models. Knockout of the multidrug resistance-2 gene (Mdr2 −/−) impairs bile salt secretion and results in intrahepatic cholestasis and hepatitis33. However, strain background influences this phenotype. Mdr2 −/− mice on an FVB/N background develop severe chronic hepatitis that progresses to HCC, whereas the disease is muted in mice on a B6 background34. FVB mice also were used to demonstrate that common bile duct ligation results in the most extreme cholestatic disease (including prominent fibrosis), followed by chemical injury with CCl4, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, and α-naphthyl-isothiocyanate35.

Alcoholic Liver Disease

Most studies of ALD utilize B6 mice because of their willingness to ingest ethanol compared with other strains36. However, in a comparison of 12 inbred strains, high alcohol ingestion resulted in dramatic variation in hepatic steatosis and inflammation37. NZW/Lacj was most sensitive, whereas Wsb/Eij was resistant. Among the more common strains tested, BALB/c showed intermediate ALD sensitivity, whereas C3H/HeJ and FVB/N were more resistant. It is noteworthy that 129S1Svimj mice, which have inherent defects in iron metabolism, were resistant to the high alcohol diet, demonstrating that not all types of liver injury are additive.

Baffled by NAFLD and NAFL and NASH

NAFLD is a relatively recent clinical construct arising out of the need to characterize liver disease associated with the epidemic of obesity, metabolic syndrome, and T2D. Originally, NAFLD was somewhat synonymous with benign hepatic steatosis (fatty liver), whereas the more aggressive nonalcoholic steatohepatitis (NASH) was a distinct subcomponent. Today, many investigators use the term NAFL (nonalcoholic fatty liver) to connote uncomplicated hepatic lipidosis, joining NASH as a distinct entity under the NAFLD umbrella. Others hedge their bets with the parenthetical NAFL(D). NASH was originally defined by three histologic criteria: steatosis, inflammation, and hepatocyte ballooning degeneration38. Those same three criteria are graded by pathologists semiquantitatively to form the NAFLD activity score (NAS). Under the current rubric, steatosis (0–3), hepatocyte ballooning (0–2), and inflammation (0–3) each receives an individual score, for an overall NAS range from 0 to 838. Fibrosis is a frequent outcome of chronic NASH and is considered by many an integral aspect of the disease. Scoring criteria on a 0–4 scale have been described for fibrosis, but this remains an addendum to the NAS and is not typically included within it38. Unfortunately, human NAS scoring does not translate well to mouse models. In particular, hepatocyte ballooning degeneration is lacking in most murine fatty liver models, especially those relying on diet-induced or genetically defined obesity39. This is not an insignificant consideration because hepatocyte ballooning reflects lipotoxicity and represents an inflection point in the transition from clinically static to progressive fatty liver disease40. In most DIO mouse models, excess fat is stored in discrete membrane-bound lipid droplets primarily in the form of triglycerides (i.e., benign steatosis). Sometimes this is superimposed with glycogen-mediated cytoplasmic hydropic degeneration (“cloudy swelling”), particularly in diets supplemented with excess sugars, leading to an erroneous interpretation of ballooning degeneration. There are mouse models that do produce bona fide ballooning degeneration, but these tend to rely on direct oxidative injury rather than caloric overload, and animals typically lose rather than gain weight due to hepatotoxicity. As such, they may recapitulate histologic but not metabolic features of the human disease. Here we consider a sampling of models that rely on caloric overload (in the form of excess fats and/or sugars) versus direct oxidative stress (with or without concomitant high-fat/sugar feeding).

Obesity Models of Fatty Liver Disease

Most diet-induced and genetic obesity models (e.g., ob/ob mice) produce NAFL but not NASH39. However, these models do a good job of reproducing systemic metabolic conditions associated with the human disease (e.g., obesity and insulin resistance). Fatty liver phenotypes in genetic and diet-induced models frequently (though not always) correlate with visceral adiposity. Because B6 mice are highly susceptible to DIO and fatty liver, an overwhelming majority of NAFLD studies in WT mice use the C57BL/6 strain41. In contrast, A/J mice fall at the other end of the spectrum, resisting both DIO and NAFLD. For this reason, studies into genetic determinants of basal metabolism and obesity-associated diseases often contrast findings in these two strains42. The extreme difference in obesity propensity between B6 and A/J mice has led to the development of chromosome-substitution strain (or consomic) mice on a C57BL/6 background with the exception of one A/J chromosome in order to localize genetic determinants in a systematic way43. Interestingly, the hybrid F1 offspring of B6 and A/J mice develop spontaneous insulin resistance and NAFL in a parent-specific fashion, suggesting an additional contribution of epigenetic imprinting to strain-dependent obesity phenotypes44. In a rare study contrasting B6 mice to a strain other than A/J, it was shown that high-fat diet feeding to C57BL/6 resulted in extrahepatic adiposity, liver inflammation, and fibrosis, whereas BALB/c mice developed benign steatosis only; these attributes were attributed in part to different immune cell populations reflecting known strain biases toward a Th1 (B6) or Th2 (BALB/c) phenotype45.

Oxidative Injury Models of Fatty Liver Disease

In order to induce lipotoxicity sufficient to result in hepatocyte ballooning in mice, experimental challenge beyond a high-fat/high-sugar diet usually is required. Some investigators add a hepatotoxin such as CCl4 to the mix to enhance oxidative liver injury and increase fibrosis46. Others forego the obesity component and feed mice a methionine–choline deficient (MCD), which induces NASH-like disease through loss of phosphatidylcholine precursors required for proper mitochondrial function and oxygen free radical scavenging (SAMe; glutathione)47. Although livers from MCD mice recapitulate the histologic features of NASH48, animals lose rather than gain weight, and insulin resistance and other system-wide metabolic dysfunctions associated with human NASH are not reproduced. Indeed, fat accumulation itself in this model is attributable to hepatocyte distress and not caloric overload. The Mdr2 −/− mouse, which develops cholestatic liver disease and severe oxidative stress, also displays histologic features consistent with NASH in conjunction with body wasting49. The STAM™ mouse model relies on an injection of streptozotocin to destroy pancreatic islet β cells early in life, followed by a high-fat diet. This produces severe hyperglycemia due to insulin depletion, resulting in NASH-like lesions in the liver; however, the model often is criticized because low insulin levels are more consistent with type 1 (juvenile) diabetes rather than insulin resistance and hyperinsulinemia associated with T2D and metabolic syndrome50. Because of severe cellular injury and inflammation, oxidative stress-based models also tend to induce more fibrosis than DIO models51. Almost all of the studies using the aforementioned strategies utilize B6 mice, and it is difficult to find strain comparisons. However, one study found that C57BL/6N mice on an MCD diet developed more severe lesions including steatosis and fibrosis than did C3H/HeN mice52. A related model utilizes a diet deficient in cholate and folate (CFD). In a comparison of seven strains on the CFD diet, it was found that WSB/EiJ developed the most severe disease, whereas A/J, C57BL/6, and C3H/HeJ were more resistant53. These phenotypes were attributed at least in part to endogenous iron metabolism54. It is interesting to note that WSB/EiJ mice are resistant to alcohol-induced liver injury but highly sensitive to MCD diet, highlighting the importance of genetic background when assessing responses to different liver challenges.

Hepatocellular Carcinoma

The impact of mouse strain on HCC susceptibility has received an excellent recent review elsewhere and will not be covered in depth here55. C3H mice are well known for their high incidence of both spontaneous and chemically initiated hepatocellular tumors, whereas C57BL/6, BALB/c, and A/J mice are more resistant. B6C3F1 hybrids (like those used in NTP studies) show an intermediate phenotype, with C3H-like high tumor volume but B6-like low multiplicity56. In a two-hit chemical initiation–promotion comparison, it was found that C3H mice were highly susceptible both to diethylnitrosamine (DEN) initiation and phenobarbital (PB) promotion, BALB/c were resistant to initiation but sensitive to promotion, and B6 mice resisted both57. Tumor-susceptible DBA/2 mice also are sensitive to DEN/PB initiation–promotion58. Strain differences in HCC risk occur at the level of promotion and not initiation, as few differences in metabolism and adduct formation are noted immediately after challenge with common hepatocarcinogens including DEN and aflatoxin B159. Interestingly, C3H and HCC-susceptible CBA mice show high metallothionein responses to zinc and copper exposure, whereas HCC-resistant B6 mice respond weakly to similar metal ion challenge60.

CONCLUSION

Selection of inbred mouse strain may be just as important as choosing a model in the investigation of liver disease in vivo. C57BL/6 mice are an excellent choice for some but not all models, and this strain should not simply be defaulted to based on prior literature. Other strains have unique characteristics that may make them best suited for studies of liver regeneration, toxicity, infection, metabolic disease, and cancer (see Table 1). It cannot be stressed enough that choosing the right strain will reward the investigator with better outcomes and a higher relevance to human liver disease.

Table 1.

Inbred Mice in Commonly Used Models of Human Liver Disease With Overall Strengths and Weaknesses

Strain Commonly Used Models Strengths Weaknesses
C57BL/6 Liver regeneration (PH)
DILI
Cholestasis/fibrosis (BDL)
ALD
NAFLD (susceptible)
“NASH” (MCD)
KO models		 Best-characterized inbred strain
Most KO models on B6 background
Willingly ingest alcohol
Metabolically susceptible to obesity-associated diseases (NAFLD)		 Pup mortality higher than other strains
Immune models limited to Th1 type
Sometimes defaulted to even when another strain is better suited
BALB/c Fibrosis (CCl4, TAA) More fibrosis than other strains
Th2 foil to Th1-biased B6 when comparing immune responses		 Can be difficult to handle
C3H Apoptosis (Fas)
LPS/sepsis
HCC (DEN, AFB1)		 TLR4 functionality can be selected
Highly susceptible to chemically induced HCC		 Prone to spontaneous preneoplastic and neoplastic liver lesions
A/J NAFLD (resistant)
Chronic hepatitis and hepatitis-associated HCC (Helicobacter hepaticus)		 Resistance to obesity-associated diseases serves as a foil to B6
Only model of infectious chronic hepatitis and HCC by a murine pathogen (H. hepaticus)		 Outside of metabolic studies, not as well characterized as other strains
FVB/N Cholestatic hepatitis (Mdr2 -/-)
Transgenic models		 Large and readily transfectable embryo facilitates transgene insertion Not as well characterized as other strains
Open in a new tab

AFB1, aflatoxin B1; ALD, alcoholic liver disease; BDL, bile duct ligation; CCl4, carbon tetrachloride; DEN, diethylnitrosamine; DILI, drug-induced liver injury; HCC, hepatocellular carcinoma; H. hepaticus,Helicobacter hepaticus; KO, knockout; LPS, lipopolysaccharide; MCD, methionine choline-deficient diet; MDR, multidrug resistant; NAFLD, nonalcoholic liver disease; NASH, nonalcoholic steatohepatitis; PH, partial hepatectomy; TAA, thioacetamide.

REFERENCES

  • 1. Rogers AB, Houghton J. Helicobacter-based mouse models of digestive system carcinogenesis. Methods Mol Biol. 2009;511:267–95. [DOI] [PubMed] [Google Scholar]
  • 2. Low BE, Kutny PM, Wiles MV. Simple, efficient CRISPR-Cas9-mediated gene editing in mice: Strategies and methods. Methods Mol Biol. 2016;1438:19–53. [DOI] [PubMed] [Google Scholar]
  • 3. Duan L, Davis JS, Woolbright BL, Du K, Cahkraborty M, Weemhoff J, Jaeschke H, Bourdi M. Differential susceptibility to acetaminophen-induced liver injury in sub-strains of C57BL/6 mice: 6N versus 6J. Food Chem Toxicol. 2016;98(Pt B):107–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Weber EM, Algers B, Hultgren J, Olsson IA. Pup mortality in laboratory mice—Infanticide or not? Acta Vet Scand. 2013;55:83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Tan P, Liang H, Nie J, Diao Y, He Q, Hou B, Zhao T, Huang H, Li Y, Gao X, and others. Establishment of an alcoholic fatty liver disease model in mice. Am J Drug Alcohol Abuse 2017;43(1):61–8. [DOI] [PubMed] [Google Scholar]
  • 6. Fengler VH, Macheiner T, Kessler SM, Czepukojc B, Gemperlein K, Muller R, Kiemer AK, Magnes C, Haybaeck J, Lackner C, and others. Susceptibility of different mouse wild type strains to develop diet-induced NAFLD/AFLD-associated liver disease. PLoS One 2016;11(5):e0155163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Feitelson MA, Larkin JD. New animal models of hepatitis B and C. Ilar J. 2001;42(2):127–38. [DOI] [PubMed] [Google Scholar]
  • 8. Drinkwater NR, Ginsler JJ. Genetic control of hepatocarcinogenesis in C57BL/6J and C3H/HeJ inbred mice. Carcinogenesis 1986;7(10):1701–7. [DOI] [PubMed] [Google Scholar]
  • 9. Lee GH, Drinkwater NR. The Hcr (hepatocarcinogen resistance) loci of DBA/2J mice partially suppress phenotypic expression of the Hcs (hepatocarcinogen sensitivity) loci of C3H/HeJ mice. Carcinogenesis 1995;16(8):1993–6. [DOI] [PubMed] [Google Scholar]
  • 10. Jovicic N, Jeftic I, Jovanovic I, Radosavljevic G, Arsenijevic N, Lukic ML, Pejnovic N. Differential immunometabolic phenotype in Th1 and Th2 dominant mouse strains in response to high-fat feeding. PLoS One 2015;10(7):e0134089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Bhathal PS, Rose NR, Mackay IR, Whittingham S. Strain differences in mice in carbon tetrachloride-induced liver injury. Br J Exp Pathol. 1983;64(5):524–33. [PMC free article] [PubMed] [Google Scholar]
  • 12. Szymanska H, Lechowska-Piskorowska J, Krysiak E, Strzalkowska A, Unrug-Bielawska K, Grygalewicz B, Skurzak HM, Pienkowska-Grela B, Gajewska M. Neoplastic and nonneoplastic lesions in aging mice of unique and common inbred strains contribution to modeling of human neoplastic diseases. Vet Pathol. 2014;51(3):663–79. [DOI] [PubMed] [Google Scholar]
  • 13. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, and others. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 1998;282(5396):2085–8. [DOI] [PubMed] [Google Scholar]
  • 14. Yohe HC, O’Hara KA, Hunt JA, Kitzmiller TJ, Wood SG, Bement JL, Bement WJ, Szakacs JG, Wrighton SA, Jacobs JM, and others. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity. Am J Physiol Gastrointest Liver Physiol. 2006;290(6):G1269–79. [DOI] [PubMed] [Google Scholar]
  • 15. Hoenerhoff MJ, Hong HH, Ton TV, Lahousse SA, Sills RC. A review of the molecular mechanisms of chemically induced neoplasia in rat and mouse models in National Toxicology Program bioassays and their relevance to human cancer. Toxicol Pathol. 2009;37(7):835–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Surwit RS, Wang S, Petro AE, Sanchis D, Raimbault S, Ricquier D, Collins S. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci USA 1998;95(7):4061–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Buchner DA, Burrage LC, Hill AE, Yazbek SN, O’Brien WE, Croniger CM, Nadeau JH. Resistance to diet-induced obesity in mice with a single substituted chromosome. Physiol Genomics 2008;35(1):116–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Millward CA, Burrage LC, Shao H, Sinasac DS, Kawasoe JH, Hill-Baskin AE, Ernest SR, Gornicka A, Hsieh CW, Pisano S, and others. Genetic factors for resistance to diet-induced obesity and associated metabolic traits on mouse chromosome 17. Mamm Genome 2009;20(2):71–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Mervai Z, Egedi K, Kovalszky I, Baghy K. Diethylnitrosamine induces lung adenocarcinoma in FVB/N mouse. BMC Cancer 2018;18(1):157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Sachse B, Meinl W, Glatt H, Monien BH. Ethanol and 4-methylpyrazole increase DNA adduct formation of furfuryl alcohol in FVB/N wild-type mice and in mice expressing human sulfotransferases 1A1/1A2. Carcinogenesis 2016;37(3):314–9. [DOI] [PubMed] [Google Scholar]
  • 21. Michalopoulos GK. Hepatostat: Liver regeneration and normal liver tissue maintenance. Hepatology 2017;65(4):1384–92. [DOI] [PubMed] [Google Scholar]
  • 22. Marlini M, Mabuchi A, Mallard BL, Hairulhisyam N, Akashi-Takamura S, Harper JL, Wheatley AM. Delayed liver regeneration in C3H/HeJ mice: Possible involvement of haemodynamic and structural changes in the hepatic microcirculation. Exp Physiol. 2016;101(12):1492–505. [DOI] [PubMed] [Google Scholar]
  • 23. Jaeschke H. Acetaminophen: Dose-dependent drug hepatotoxicity and acute liver failure in patients. Dig Dis. 2015;33(4):464–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Williams CD, Koerner MR, Lampe JN, Farhood A, Jaeschke H. Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation. Toxicol Appl Pharmacol. 2011;257(3):449–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Kwon J, Weisel CP, Morandi MT, Stock TH. Source proximity and meteorological effects on residential outdoor VOCs in urban areas: Results from the Houston and Los Angeles RIOPA studies. Sci Total Environ. 2016;573:954–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Lee VM, Cameron RG, Archer MC. Zonal location of compensatory hepatocyte proliferation following chemically induced hepatotoxicity in rats and humans. Toxicol Pathol. 1998;26(5):621–7. [DOI] [PubMed] [Google Scholar]
  • 27. Lua I, Li Y, Zagory JA, Wang KS, French SW, Sevigny J, Asahina K. Characterization of hepatic stellate cells, portal fibroblasts, and mesothelial cells in normal and fibrotic livers. J Hepatol. 2016;64(5):1137–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Adkins Y, Schie IW, Fedor D, Reddy A, Nguyen S, Zhou P, Kelley DS, Wu J. A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. Lab Invest. 2013;93(12):1313–22. [DOI] [PubMed] [Google Scholar]
  • 29. Ikenaga N, Peng ZW, Vaid KA, Liu SB, Yoshida S, Sverdlov DY, Mikels-Vigdal A, Smith V, Schuppan D, Popov YV. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 2017;66(9):1697–708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Wang K. Autophagy and apoptosis in liver injury. Cell Cycle 2015;14(11):1631–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Han D, Ybanez MD, Ahmadi S, Yeh K, Kaplowitz N. Redox regulation of tumor necrosis factor signaling. Antioxid Redox Signal. 2009;11(9):2245–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Weerasinghe SV, Park MJ, Portney DA, Omary MB. Mouse genetic background contributes to hepatocyte susceptibility to Fas-mediated apoptosis. Mol Biol Cell 2016;27(20):3005–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Li X, Liu R, Huang Z, Gurley EC, Wang X, Wang J, He H, Yang H, Lai G, Zhang L, and others. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and human. Hepatology 2018;68(2):599–615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Potikha T, Stoyanov E, Pappo O, Frolov A, Mizrahi L, Olam D, Shnitzer-Perlman T, Weiss I, Barashi N, Peled A, and others. Interstrain differences in chronic hepatitis and tumor development in a murine model of inflammation-mediated hepatocarcinogenesis. Hepatology 2013;58(1):192–204. [DOI] [PubMed] [Google Scholar]
  • 35. Chang ML, Yeh CT, Chang PY, Chen JC. Comparison of murine cirrhosis models induced by hepatotoxin administration and common bile duct ligation. World J Gastroenterol. 2005;11(27):4167–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Holleran KM, Winder DG. Preclinical voluntary drinking models for alcohol abstinence-induced affective disturbances in mice. Genes Brain Behav. 2017;16(1):8–14. [DOI] [PubMed] [Google Scholar]
  • 37. Tsuchiya M, Ji C, Kosyk O, Shymonyak S, Melnyk S, Kono H, Tryndyak V, Muskhelishvili L, Pogribny IP, Kaplowitz N, and others. Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice. Hepatology 2012;56(1):130–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, and others. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41(6):1313–21. [DOI] [PubMed] [Google Scholar]
  • 39. Santhekadur PK, Kumar DP, Sanyal AJ. Preclinical models of non-alcoholic fatty liver disease. J Hepatol. 2018;68(2):230–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Farrell GC, van Rooyen D, Gan L, Chitturi S. NASH is an inflammatory disorder: Pathogenic, prognostic and therapeutic implications. Gut Liver 2012;6(2):149–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Van Herck MA, Vonghia L, Francque SM. Animal models of nonalcoholic fatty liver disease—A starter’s guide. Nutrients 2017;9(10). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. Kondo H, Minegishi Y, Komine Y, Mori T, Matsumoto I, Abe K, Tokimitsu I, Hase T, Murase T. Differential regulation of intestinal lipid metabolism-related genes in obesity-resistant A/J vs. obesity-prone C57BL/6J mice. Am J Physiol Endocrinol Metab. 2006;291(5):E1092–9. [DOI] [PubMed] [Google Scholar]
  • 43. Nadeau JH, Singer JB, Matin A, Lander ES. Analysing complex genetic traits with chromosome substitution strains. Nat Genet. 2000;24(3):221–5. [DOI] [PubMed] [Google Scholar]
  • 44. Hines IN, Hartwell HJ, Feng Y, Theve EJ, Hall GA, Hashway S, Connolly J, Fecteau M, Fox JG, Rogers AB. Insulin resistance and metabolic hepatocarcinogenesis with parent-of-origin effects in AxB mice. Am J Pathol. 2011;179(6):2855–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Jovicic N, Jeftic I, Jovanovic I, Radosavljevic G, Arsenijevic N, Lukic ML, Pejnovic N. Differential immunometabolic phenotype in Th1 and Th2 dominant mouse strains in response to high-fat feeding. PLoS One 10(7):e0134089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Tsuchida T, Lee YA, Fujiwara N, Ybanez M, Allen B, Martins S, Fiel MI, Goossens N, Chou HI, Hoshida Y, and others. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018;69(2):385–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Caballero F, Fernandez A, Matias N, Martinez L, Fucho R, Elena M, Caballeria J, Morales A, Fernandez-Checa JC, Garcia-Ruiz C. Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: Impact on mitochondrial S-adenosyl-L-methionine and glutathione. J Biol Chem. 2010;285(24):18528–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Tanaka N, Takahashi S, Zhang Y, Krausz KW, Smith PB, Patterson AD, Gonzalez FJ. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochim Biophys Acta 2015;1852(7):1242–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Wang X, Hausding M, Weng SY, Kim YO, Steven S, Klein T, Daiber A, Schuppan D. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid Redox Signal. 2018;28(2):87–109. [DOI] [PubMed] [Google Scholar]
  • 50. Saito T, Muramatsu M, Ishii Y, Saigo Y, Konuma T, Toriniwa Y, Miyajima K, Ohta T. Pathophysiological analysis of the progression of hepatic lesions in STAM mice. Physiol Res. 2017;66(5):791–9. [DOI] [PubMed] [Google Scholar]
  • 51. Reid DT, Eksteen B. Murine models provide insight to the development of non-alcoholic fatty liver disease. Nutr Res Rev. 2015;28(2):133–42. [DOI] [PubMed] [Google Scholar]
  • 52. Yamazaki Y, Kakizaki S, Takizawa D, Ichikawa T, Sato K, Takagi H, Mori M. Interstrain differences in susceptibility to non-alcoholic steatohepatitis. J Gastroenterol Hepatol. 2008;23(2):276–82. [DOI] [PubMed] [Google Scholar]
  • 53. Tryndyak VP, Latendresse JR, Montgomery B, Ross SA, Beland FA, Rusyn I, Pogribny IP. Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet. Toxicol Appl Pharmacol. 2012;262(1):52–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Shpyleva S, Pogribna M, Cozart C, Bryant MS, Muskhelishvili L, Tryndyak VP, Ross SA, Beland FA, Pogribny IP. Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism. J Nutr Biochem. 2014;25(12):1235–42. [DOI] [PubMed] [Google Scholar]
  • 55. Maronpot RR. Biological basis of differential susceptibility to hepatocarcinogenesis among mouse strains. J Toxicol Pathol. 2009;22(1):11–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Pugh TD, Goldfarb S. Growth kinetics of microscopic hepatocellular neoplasms in carcinogen-resistant and carcinogen-responsive strains of mice. Cancer Res. 1992;52(2):280–4. [PubMed] [Google Scholar]
  • 57. Lee GH, Nomura K, Kitagawa T. Comparative study of diethylnitrosamine-initiated two-stage hepatocarcinogenesis in C3H, C57BL and BALB mice promoted by various hepatopromoters. Carcinogenesis 1989;10(12):2227–30. [DOI] [PubMed] [Google Scholar]
  • 58. Diwan BA, Rice JM, Ohshima M, Ward JM. Interstrain differences in susceptibility to liver carcinogenesis initiated by N-nitrosodiethylamine and its promotion by phenobarbital in C57BL/6NCr, C3H/HeNCrMTV- and DBA/2NCr mice. Carcinogenesis 1986;7(2):215–20. [DOI] [PubMed] [Google Scholar]
  • 59. Borroz KI, Ramsdell HS, Eaton DL. Mouse strain differences in glutathione S-transferase activity and aflatoxin B1 biotransformation. Toxicol Lett. 1991;58(1):97–105. [DOI] [PubMed] [Google Scholar]
  • 60. Farr C, Hunt DM. Genetic differences in zinc and copper induction of liver metallothionein in inbred strains of the mouse. Biochem Genet. 1989;27(3-4):199–217. [DOI] [PubMed] [Google Scholar]

Articles from Gene Expression are provided here courtesy of Cognizant Communication Corporation

RESOURCES