|Year : 2016 | Volume
| Issue : 2 | Page : 51-57
A review of nonalcoholic fatty liver disease - genetics and animal models
Ze Zheng, Xiaobo Wang, Bishuang Cai
Department of Medicine, Columbia University, New York, NY 10032, USA
|Date of Submission||13-May-2016|
|Date of Acceptance||01-Jun-2016|
|Date of Web Publication||4-Jul-2016|
Department of Medicine, Columbia University, New York, NY 10032
Source of Support: None, Conflict of Interest: None
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from simple NAFL to nonalcoholic steatohepatitis, to irreversible cirrhosis. NAFLD is the most common chronic liver disease in developed countries and is considered as the hepatic manifestation of cardiovascular disease and metabolic syndrome. In the pathogenesis of NAFLD, hepatic lipid accumulation results from an imbalance between lipid synthesis, storage, oxidation, and/or secretion, and eventually triggers hepatic inflammation and injury. The increasing incidence of NAFLD etiological studies has shown that obesity, hepatitis C, and cryptogenic cirrhosis are associated with NAFLD. Here, we provide a comprehensive NAFLD review that covers the population genetics, genome-wide associated study, epidemiology, pathophysiology of the disease progression, and current existing animal models.
Keywords: Animal model, genome-wide association study, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity
|How to cite this article:|
Zheng Z, Wang X, Cai B. A review of nonalcoholic fatty liver disease - genetics and animal models. Environ Dis 2016;1:51-7
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver diseases ranging from simple NAFL to nonalcoholic steatohepatitis (NASH), to irreversible cirrhosis. , NAFLD is the most common chronic liver disease in developed countries and is considered as the hepatic manifestation of cardiovascular disease and metabolic syndrome. ,, In the pathogenesis of NAFLD, hepatic lipid accumulation results from an imbalance between lipid synthesis, storage, oxidation, and/or secretion, and eventually triggers hepatic inflammation and injury. , The progression of NASH is explained by a "two-hit" working model.  According to this model, steatosis represents the "first hit," which increases the vulnerability of the liver to various "second hits" induced by endotoxin, saturated fatty acids, inflammatory cytokines, hepatocyte organelle malfunction, oxidative stress, endoplasmic reticulum (ER) stress, or other liver injuries. The "second hit" in turn leads to hepatic inflammation and fibrosis, the key features of NASH. 
The first reported NAFLD on adult was in 1980,  and it has become a well-recognized common liver disorder in the past 30 years. Up to 30% of adults and nearly 5% children were estimated to be affected by NAFLD in the general population of different geographic regions and ethics from Europe, the US to Asia-Pacific region.  Epidemic studies have shown that as much as 75% of obese adult and 53% of obese children affected by NAFLD in Italia and US. ,, Some studies also have shown that NAFLD is more common in Hispanic adolescents than non-Hispanic white and black, and with increasing prevalence in obese adolescent boys than in girls. , In adult population, men also more susceptible to have NAFLD than women do. , The increasing incidence of NAFLD etiological studies has shown that hepatitis C and cryptogenic cirrhosis, half of which are associated with NAFLD, are the most common etiologies of hepatocellular carcinoma in the US. 
Here, we summarize the current views on NAFLD from the perspectives covering the population genetics, genome-wide associated study, epidemiology, pathophysiology of the disease progression, and current existing animal models.
| Candidate Genes and Genome-Wide Association Studies|| |
Although many genes have been hypothesized to be involved in the occurrence and disease progression of NAFLD, many of these genes have not been studied with detail mechanisms and have only been associated based on findings in genome-wide association studies (GWASs). However, one gene of particular interest is patatin-like phospholipase domain containing 3 gene (PNPLA3), which has been suspected in the pathogenesis of NASH. This candidate gene was originally identified through GWAS, but till recently, it has become the focus of many candidate gene studies.  Many of these studies have found that PNPLA3 has been associated with NAFLD/NASH in both adults and children alike through replicated studies. , Many of these studies also independently found increased alanine transferase and aspartate transaminase levels, which are implicated in the progression of the disease. ,,
Previous studies showed that genetic variants could influence risk of NAFLD by using GWA analysis of noninvasive hepatic steatosis measured by computed tomography (CT) in a large population sample. , Clinically biopsy-proven NAFLD subjects showed hepatic steatosis associated variants at five loci in or near NCAN, GCKR, LYPLAL1, and PNPLA3 exhibit abnormalities in serum lipid or glycemic and anthropometric traits. These common genetic variants affected the risk of CT-assessed NAFLD, but not uniformly associated with histologically assessed NASH and hepatic fibrosis and other phenotypes, which suggested that these phenotypes could be influenced by genetic heterogeneity in the related signaling pathways.
Interestingly, the study has shown that the heritability of CT hepatic steatosis has a genetic basis associated with genetic variants by estimating three family-based cohorts. About 26-27% of the genetic variation in the CT-assessed hepatic steatosis is heritable. More specifically, the GWA analyses carried out the genetic loci of rs738409 is in PNPLA3, rs4240624 is near PPP2R3B, and rs2228603 is near NCAN associated with CT hepatic steatosis, and many other single nucleotide polymorphisms (SNPs) listed in [Table 1]. ,,,
|Table 1: Genome-wide significant variants associated with nonalcoholic fatty liver disease phenotypes|
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Another study showed different genetic loci associated NAFLD by GWAS of liver histology in 236 non-Hispanic white women with NAFLD on 324,623 SNPs from 22 autosomal chromosomes.  The results were carefully adjusted by age, body mass index, diabetes, waist/hip ratios, and levels of glycated hemoglobin, which increased the quality of the data analyses. Several different genetic loci were found to associate with NAFLD phenotypes. They are farnesyl diphosphate farnesyl transferase 1, COL13A1, EFCAB4B, and alanine aminotransferase (ALT) [Table 1].
Although the genetic loci found in these two studies were different without any overlapping which could be caused by many reasons, we still can see the genetic traits associated with the risk and progression of NAFLD. However, the two studies were based on different sampling, and some bias existed. For example, the study done by Chalasani et al.  was based on only white female patients which could be very different from the male metabolic features. Although they did not include SNPs data from the X chromosome, it does not mean it has been done without gender bias since there are still many other gene expression that could be influenced by the gene in X or Y chromosomes.
| Genomics of the phenotype|| |
In the GWAS, many phenotypes of NAFLD were found to be associated with various SNPs [Table 1]. Of these, rs738409, rs2228603, rs4240624, rs2645424 were associated with hepatic steatosis. , Many of those individuals with hepatic steatosis typically have a benign prognosis, with many remaining stable.  However, a couple of those just listed (rs738409 and rs2228603) along with rs12137855, rs780094, rs2645424 (lobular inflammation only), rs1227756 (lobular inflammation only), and rs343064 (fibrosis only) were associated with lobular inflammation and fibrosis. Several SNPs were implicated in increased levels of aspartate aminotransferase, which are associated with NASH phenotype. SNPs associated with lobular inflammation/fibrosis indicate a NASH phenotype that can either have regression of fibrosis or progression fibrosis. Progression of fibrosis can ultimately lead to cirrhosis of the liver, implicated in a less favorable prognosis (liver failure, hepatoma, and/or death). 
Although GWAS are informative, these studies did not take into account variations among ethnicities. One study looked only at histological data from non-Hispanic white women, which is informative for non-Hispanic white women but not applicable to those people of other ethnicities or gender.  On the other hand, the other GWAS did utilize varying populations (persons living in Reykjavik, Iceland, persons from an Old Order Amish community, persons living in Framingham, Massachusetts, and others).  This, however, could be considered as a disadvantage where differences among these groups are not taken into consideration, and associated SNPs cannot apply to a specific ethnicity but rather the global population. Further studies should be performed to determine associations between specific ethnic groups/populations, SNPs, and NAFLD to make conclusions more informative and applicable.
It is important to note that many other GWAS have been performed to address associations of variants with phenotypes of NAFLD. However, it was more important to address a couple of these studies and elaborate on those findings.
Currently, molecular testing to identify genes associated with NAFLD is not available. However, a direct-to-consumer testing company, 23andMe, allows an individual to submit a cheek swab to test some of the SNPs associated with complex disorders, one of those being NAFLD.  Regarding NAFLD, they look for one SNP, rs3772622, found to be associated with NAFLD in Asians in one study,  which is interesting considering the great deal of other SNPs that have been thought to be associated with the disease.
The results they provide from their test determine someone's odds of getting NAFLD at some point in their life, but these results are not diagnostic. They also may not be informative considering the SNP tested has not been studied in other ethnicities. Aside from the already stated issues, this test may have molecular validity, but it has neither clinic validity nor utility. GWAS have only found certain SNPs to be associated with certain phenotypes, but this does not mean they are the real factors that cause these diseases.
| Risk factors|| |
As previously noted, NAFLD, specifically NASH, develops as a result of "two hits" based on a two-hit model. The first "hit" resulting from some genetic aspects, and the second "hit" resulting from an external risk factor. Many studies have focused on these various risk factors to determine the degree of association with the phenotype. , [Table 1] lists these associated risk factors.
Of all mentioned risk factors, obesity is the most strongly associated with NAFLD [Table 2]. This is a big concern since nearly one-third of adults in the United States are obese. In a study looking at obese adults, 57-74% were found to have NAFLD.  Of those adults with NASH, 40-100% were reported as obese, with the range depending on the definition of obesity used.  However, a significant number of individuals with newly diagnosed diabetes (62%) or impaired glucose tolerance (43%) were found to have a higher prevalence of NAFLD. , In one study, it was found that 49% of individuals with Type 2 diabetes also had hepatic steatosis.  In general, associations between liver disease and insulin resistance (IR) or hyperinsulinemia, even in the absence of obesity, further confirmed diabetes as a risk factor. Hypertension, hyperlipidemia, and hypothyroidism have all been associated with the presence of NAFLD.
|Table 2: Nongenetic, external risk factors associated with nonalcoholic fatty liver disease|
Click here to view
For other risk factors, studies have been performed to reveal the association with NAFLD. In one large cohort study, an association between a history of smoking and advanced liver fibrosis among individuals with NAFLD was found, indicating the possible role of smoking in NAFLD progression.  Although many studies have revealed the association of NAFLD with obesity and sleep apnea, one study specifically looked at obstructive sleep apnea and hypoxia and their association with NAFLD phenotype. They found that, regardless of body weight, there was a higher prevalence of NASH among those with severe obstructive sleep apnea.  Some studies have considered birth weight as a factor for influencing the development of metabolic syndrome, associated with the development of NAFLD, and have found that low birth weight is associated with the increased risk metabolic syndrome.  Recent studies using rat models have implicated maternal high-fat intake as a risk factor for small offspring born with metabolic syndrome similar to that in humans.  Finally, although one study has found a difference between adult men and women regarding NASH prevalence in the spectrum of NAFLD,  other studies have been unable to identify a true difference among gender and NASH development.  Therefore, gender can not be considered as a risk factor.
Environmental factors also accelerate the development of NAFLD. Air pollution have been shown to associate with IR and elevated ALTs disease in the general population. ,, Experimental studies using in vitro and in vivo animal models discovered fine airborne particulate matters with aerodynamic diabetes <2.5 μm (PM 2.5 ) can activate cellular ER stress response in lung and liver tissues, impair liver glucose metabolism, and induce NASH-like phenotype and liver fibrosis. ,,
| Epidemiology|| |
A few studies have demonstrated that NAFLD and associated phenotypes are found to cluster within families. For instance, a study found the presence of NASH and/or cirrhosis in seven out of eight families,  while another study found that out of the 90 NASH patients, 18% had an affected first-degree relative.  It seems that this clustering could be due to other associated risk factors found regularly within a family rather than the likelihood of a genetic component. However, studies exploring ethnic differences associated with the prevalence of NAFLD and associated phenotypes have revealed that a genetic component is likely implicated in predisposing individuals to NAFLD.
From a genetic standpoint, ethnic variations result in differing prevalence and incidence of NAFLD. Although it is also true that the number and the degree of other risk factors associated with NAFLD vary among ethnic groups, some studies have revealed the importance of an underlying genetic etiology in NAFLD. , In one study, the prevalence of cirrhosis among Hispanic-Americans was 3-fold higher than that of European-Americans, while African-Americans had a prevalence that was 4-fold lower than that of European-Americans.  All groups had a similar prevalence of Type 2 diabetes, a risk factor for NAFLD and associated phenotypes, further implying a possible genetic etiology. Although we have discussed GWAS elsewhere, one in particular, derived from the Dallas Heart Study, found that the SNP rs738409 in the PNPLA3 gene was more commonly found in Hispanics than in individuals of European ancestry who had a lower frequency of the variant, particularly, African American, having the lowest frequency. 
| Disease progression|| |
In most cases, the NAFLD progress is similar to [Figure 1]. The majority of cases of hepatic steatosis will remain stable, with some developing NASH. Of all cases of NASH, 25-35% will progress to fibrosis and 9-20% will progress to cirrhosis.  Ultimately, 22-33% of cirrhosis will either lead to death from complications of liver failure or require a liver transplant.  One area of particular interest in studying the progression of NAFLD includes the genes involved in the oxidation of free fatty acids (FFA). The genes and associated proteins specifically affect oxidant load in individuals, where lack of FFA oxidation can lead to fat accumulation in the liver, but increased FFA oxidation can lead to oxidative stress, both of which are implicated in disease progression. 
| Animal models|| |
Animal models are very powerful tools for studying pathological progression and potential therapeutic strategies of human diseases including NAFLD. However, there is no single animal model can reflect the complicated histological and pathophysiological features of human NASH phenotypes, but only partially displays some features of the phenotypes. 
The currently available genetic animal models used for studying NAFLD have been generated to mimic some of the human NASH phenotypes, such as acyl-coenzyme A oxidase null mice which had deletion of the enzyme that limits the rate of peroxisomal fatty acid β-oxidation;  methionine adenosyltransferase-1A null mice which had deletion of the liver-specific enzyme that catalyzes the formation of primary methyl donor S-adenosylmethionine;  nuclear respiratory factor 1 null mice which had deletion of a transcription factor that regulates the genes expression involved in the response of oxidative stress;  phosphatase and tensin homolog deleted on chromosome 10 (PTEN) null mice which lacked a lipid phosphatase which negatively regulates phosphatidylinositol 3-kinase-AKT prosurvival pathway; leptin-deficient ob/ob mice, leptin receptor db/db mice, and cAMP-responsive element-binding protein 3-like 3 (CREB3L3, or CREBH) null mice which develop severe NASH and hyperlipidemia under the atherogenic high-fat (AHF) diet or other acute stress conditions [Table 3]. ,,
Since NAFLD is a metabolic stress-inducible disease, there are also several dietary animal models have been commonly used, such as methionine- and choline-deficient diet,  high-fat diet,  AHF diet,  and ketogenic high-fat diet.  Previous studies showed the important role of fructose in the development of fatty liver and NASH,  and high cholesterol diet significantly increased liver fibrosis in addition to high-fat induced obesity in nongenetically modified mice.  Combining high-fat and high cholesterol causes mice gain weight and develop IR, hepatic steatosis, inflammation, and early fibrosis. The dietary stress can serve as the "secondary hit" for the NAFLD progression in the "two-hit" model [Table 3].
To study the early stage of the NASH pathophysiological development, several quickly responsible steatosis model have been widely used, such as overnight fasting,  tunicamycin intraperitoneal injection [Table 3]. ,
These models also have been widely used for combining with the genetic deficient animal model, which provides more information to study the pathogenesis of the NAFLD progression. However, many limitations existed for the animal models about whether the model really reflects the etiology since there were too many manipulations have done by the complicated animal model-generating procedures. There are many other concerns. For example, many signaling pathways are not conserved from mouse, and other species, to human. We have to wisely design and use the animal model to optimize the efficiency and scientificity of our translational medical research to study human diseases by using in vivo models.
| Summary|| |
Based on the above summary, it would be beneficial to perform further molecular and animal studies to address genes associated with NAFLD through SNPs found in GWAS. This could be performed by inducing some of these genetic changes through, for example, PNPLA3 knock-in mice revealed its important function in steatohepatitis,  and studies involving other candidate gene knock-in mice with the point mutation of interest based on SNPs associated with the phenotype. Further, it would be interesting to study these knock-in mice in conjunction with exposure to associated risk factors. Comparative studies looking at those mice with no knock-in versus those with the knock-in exposed to various risk factors may provide greater insight on how the disease develops. Although mouse models and other in vivo studies have addressed the phenotype, taking it another step further and developing ways to study the SNPs associated with NAFLD are essential. The approaches that have been used thus far to address NAFLD are beneficial to discovering more about the phenotype. However, these studies are limited because they can not be completely translated into human care.
Although it is difficult to make an accurate prediction, it seems that NAFLD and its associated phenotypes may be difficult to completely cure. This is primarily due to the complex nature of the disease, resulting from many genetic and environmental factors. It is more likely that treatments to manage the disease would be the course of action in the near future rather than a cure that completely eliminates the disease. Liver transplant is currently available for those with severe cirrhosis of the liver, but this is an unrealistic treatment for fatty liver and NASH given that the risk to benefit ratio for such a procedure. Until we are truly able to understand the mechanisms that result in NAFLD, management of symptoms will be the primary focus.
We thank Dr. Derek Wildman for his critical suggestions, and Dr. Ira Tabas for his support of writing this Review
Financial support and sponsorship
Portions of this work were supported by Berrie Scholars Award from The Russell Berrie Foundation to Ze Zheng and American Heart Association Grant 15POST25620024 to Bishuang Cai.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]