The prevalence of predictive metabolic diseases, especially dyslipidemias and nonalcoholic fatty liver disease (NAFLD), has increased worldwide [
This pathology has drawn attention in recent years. Diagnosis and assessment of NAFLD can be performed based on physical examination, history of the disease, ultrasound examination, and hepatic imaging [
The pathophysiology of NAFLD is associated with unhealthy lifestyles, which combine sedentary lifestyle, hypercaloric diets, excessive saturated fat, refined carbohydrates, and high fructose intake as a food additive to various processed products [
Although the etiologies of dyslipidemias and NAFLD are complex and multifactorial, these diseases contain an important genetic component that is influenced by environmental factors and life habits, especially the food consumption profile [
Improved knowledge of the disease and its complementary data to elucidate the NAFLD pathogenesis have led to an increase in the animal models in recent years [
Taking into account the increase in studies with NAFLD, the objective of this study was to investigate the different study designs that targeted the diet relationship with the appearance of NAFLD experimentally in rats.
This review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement according to Moher et al., 2009 [
For the eligibility of publications, each title and abstract was read exhaustively to confirm whether they addressed the guiding question of this research and whether it would meet the inclusion and exclusion criteria established. Then, the same happened to the stage of inclusion of the articles. The selection of studies is shown in Figure
Flow diagram for identification, screening, eligibility, and analysis of studies included in the review.
The following keywords or descriptors were used in the Health Sciences Descriptors (DeCS) of the Virtual Health Library: “NAFLD”, “diet”, and “rat model”.
The search in literature was executed by two investigators in the databases: Cochrane Library, Google Scholar, and PubMed for studies published before 28 Mai 2018 and addressing the NAFLD associated with rat model. The following combined keywords were used to search the literature: (“NAFLD”, “diet”, and “rat model”). Figure
Through the search carried out in PUBMED, 436 articles were found, of which 89 articles were not related to the theme, 8 articles were repeated, 2 articles were not available, 2 articles were excluded due to the used diet, which induces alcoholic liver disease (ALD) and thus was not the focus of this review, and 313 were related to the subject, but they were testing other compounds. This way, 14 articles were analyzed (Figure
As for the articles discussing diet and the onset of NAFLD, 1 used the iron-fructose-enriched diet (Ackerman et al., 2005) [
Characteristics of the studies included in this study.
Authors and year of publication | Title of the article | Objective | Diet model | Results |
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Kirsch et al., 2003 [ | Nutritional model of non-alcoholic steatohepatitis: species studies, strains and sex differences | To investigate the differences between species, lineages, and sex in the nutritional model of diet deficient in methionine choline to induce nonalcoholic steatohepatitis (NASH). | They were fed with a diet deficient in methionine and choline; the control group received an identical diet to which choline bitartrate (2 g / kg) and DL-methionine (3 g / kg) were added. | The present study has demonstrated profound species, strain, and sex differences in the MCD nutritional model of NASH. |
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Ackerman et al., 2005 [ | Hepatic Effects of Blood Pressure and Reduction of Plasma Triglycerides | To characterize hepatic pathology and function, hepatic lipid composition and hepatic iron concentration, and fasting plasma insulin changes occurring in rats as a result of the fructose-enriched diet, with and without therapeutic maneuvers to reduce blood pressure and plasma triglycerides. | Diet enriched with fructose (as supplied by Harlan Teklad) 20.7% (by weight basis) of protein (as casein), 5% fat (as lard), 60% carbohydrates (as fructose), 8% cellulose, 5% mineral blend, and 1% blend of vitamins. This diet contains 50 mg of iron in 1 kg of diet. For 5 weeks. | This study demonstrates that the model of fructose-treated rats can be a suitable model for studying various aspects of human NAFLD. |
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Zou. et al., 2006 [ | High-fat emulsion-induced rat model of non-alcoholic steatohepatitis | The objective of the present study is to produce a practical and repetitive experimental rat model for steatohepatitis by designing a high-fat emulsion containing high fat, sucrose, and protein. | The rats were divided into normal control group (NC group) and hyperlipid emulsion model group (HF group). All rats received standard ration and water. In addition, they had free access to a sucrose solution (18%). Model mice were orally treated with the high-fat emulsion (10 ml / kg) once daily. For 6 weeks. | A new rat model of steatohepatitis was established. This model provides new opportunities to study the pathogenesis and treatment. |
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De Lima et al., 2008 [ | A model of NASH rodents with cirrhosis, oval cell proliferation and hepatocellular carcinoma | Produce a mouse model of NASH, cirrhosis, and HCC. | Diet rich in fat (35% total fat, 54% trans fatty acid) and choline-deficient for 16 weeks | Our initial experience with this model demonstrates the development of histological NASH with cirrhosis, oval cell proliferation, and CK 19 positive hepatocellular carcinoma. |
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Xu et al., 2009 [ | Characterization of High-Fat, Diet-Induced, Non-alcoholic Steatohepatitis with Fibrosis in Rats | Create a new NASH model by feeding animals on a high-fat diet (DHC), with a hope of reproduction as key features of human NASH for future research. | DHC was composed of the following energy sources: 52% were provided by carbohydrates, 30% by fat, and 18% by protein (total calories: 4.8 kcal/g). Comparison with the diet deficient in methionine-choline. | In conclusion, we created a practically simple but accurate rat NASH model. It reproduced the pathological sequence of events typical of human NASH. |
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McDonald et al., 2011 [ | Adverse metabolic effects of a high-calorie, high-fat diet (HFD) in rodents precede observable changes in body weight | The specific objective was to determine the impact of a lifetime exposure to a hypercaloric, DH on adiposity, its distribution, and its glycemic control markers | Hyperlipid diet with 5% fat energy in the control group and a hypercaloric diet, rich in 41% fat, for 39 weeks. | In conclusion, after only 4 weeks, animals fed on a HFD from weaning had increased intra-abdominal fat, which preceded an increase in overall body weight and was accompanied by metabolic abnormalities including high TG and hyperglycemia in response to a glucose challenge. |
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Wu et al., 2011[ | Hepatic steatosis: an experimental model for quantification | Introduce an experimental method to quantify hepatic steatosis in rats and provide an alternative experimental model in the following studies. | Two groups fed with commercial diet and choline/methionine deficient-diet (DMC) for two weeks. | By this model, researchers can directly measure the degree of steatosis with a lesser concern about heterogeneous fatty infiltration and provide a continuous but not categorical measurement of hepatic steatosis. |
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Kucera, Cervinkova, 2014 [ | Experimental models of non-alcoholic fatty liver disease in rats | This article reviews the widely used experimental models of NAFLD in rats. We discuss the nutritional, genetic, and combined models of NAFLD and its pros and cons. | Diets high in fat; diet rich in fructose/sucrose; diet deficient in methionine and choline; atherogenic diets; genetic and combined models. | Although there is no ideal model for human nonalcoholic fatty liver disease that reflects all the clinical aspects of human disease, choosing an appropriate model for studying particular events of NAFLD while respecting its limitations has contributed greatly to the understanding of this disease and its progression and treatment. |
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Torres-Vilalobos G, et al., 2015[ | High-fat combined diet and sustained high sucrose consumption promotes NAFLD | To evaluate the impact of 4 different diets on the production of NAFLD with emphasis on a high combined consumption of high fat and sustained sucrose. | (1) Control diet. (2) High fat and cholesterol + 5% sucrose diet in drinking water. (3) High-fat corn starch diet + 5% sucrose in drinking water. (4) Food diet + 20% sucrose in drinking water for 90 days. | The HFC diet with combination of high fat and high sucrose is more effective in producing NAFLD compared with a high-sucrose diet only. |
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Lee et al., 2015 [ | Histological and Metabolic Breakdown in high-fat, high-fructose and combined dietary animal models | To evaluate and compare the differences in the induction of histological and metabolic characteristics induced by the combined diets to characterize the resulting NAFLD and NASH mouse models. | G1: normal ration, G2: hyperlipid diet fed on high-fat diet (60% total calories), | Intrahepatic inflammation and metabolic derangements were more prominent in the HF and HFr combination model than in the HF monodiet model. |
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Mikhail et al., 2017 [ | Animal Models of Non-Alcoholic Fatty Liver Disease - A Beginner’s Guide | This review provides a brief overview of the most commonly used animal models in NDFL research and maternal health care, following the broader maritime guidance model, focusing on the key phenotypic characteristics of each model. | Diet deficient in methionine and choline; diet deficient in hill-deficient L-amino acids; atherogenic diet; fructose; high-fat diet, variations in high-fat diet. | This review presents a brief overview of these models with a particular focus on the basic mechanisms and physical, biochemical, and histological phenotypes. |
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Eslamparast et al., 2017 [ | Independent dietary weight loss composition in the treatment of non-alcoholic fatty liver disease | Literature review evaluating the evidence behind dietary components, including meat, omega-3-rich diets, and depending on more evidence, we agree with the EASL-EASO Clinical Guidelines recommendation of the Mediterranean diet as the diet of choice in these patients. | Dietary Approach to Stop Hypertension (DASH) is a plant-rich dietary standard, Fiber Intervention (Soluble, Prebiotic), Omega-3 Intervention, Low Fat Interventions vs. Low-CHO, probiotics. | At this time, we do not have a definitive answer for the optimal proportions of total macronutrients (CHO, fat, and protein) in the diet of NAFLD patients. |
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Goossens, Jornayvaz, 2017 [ | Translational aspects of diet and non-alcoholic fatty liver disease | Discuss some key questions of the translational aspects of NAFLD research from the perspective of nutrition and dietary interventions, literature review. | High-fat, methionine-deficient diet; high cholesterol; high fructose and ketogenic content. | NAFLD is a complex disease with an increasing epidemiology. Currently, no specific therapeutic alternative has been developed, partly due to the lack of robust reproducible dietary animal models of the disease. |
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Han et al., 2017 [ | Distinction of the Metabolic Profile of the Progression of Non-Alcoholic Fatty Liver Disease from a Common Mouse Model | Perform complete metabolomic analyses on liver samples to determine which pathways are more markedly altered in the human condition and compare these changes with nonalcoholic fatty liver (NAFLD) models. | Alternately, the rats were fed on high-fat diet (high cholesterol, 18% butterfat) or methionine-choline deficient diet for eight weeks. | These results indicate that metabolites of specific pathways may be useful biomarkers for NASH progression, although these markers may not correspond to rodents. |
Dietary models are considered more similar to human metabolic diseases, but there are no standard composition and duration for these diets today: high-fat diets range from 30% to 60% fat content, including saturated fat, monounsaturated fatty acids, and polyunsaturated fatty acids, and last from a few days (short term) to more than a week (long term) [
It was observed that most articles found in the literature were related to the subject, but the studies used animal diet models to induce NAFLD in order to test compounds that interfere in the progression of the disease.
Ackerman et al. (2005) [
De Lima et al. (2008) [
The study by Wu et al. (2011) [
The diet deficient in methionine and choline (MCD) in the study by Kirsch et al. (2003) [
According to McDonald et al. (2011) [
Zou et al. (2006) [
The progression of nonalcoholic fatty liver disease (NAFLD).
The study by Kucera and Cervinkova [
In 2015, Torres-Vilalobos et al. [
Lee et al. (2015) [
Eslamparast et al. (2017) [
Studies investigating the influence of diet on liver fat content were performed using a high-calorie diet that leads to a significant increase in liver fat content. DHC is well known to induce some metabolic disorders, and the consequences are completely dependent on the composition and duration of the diet [
A broad view of the publications that study the diets used to simulate NAFLD in animals shows a break in nutritional, genetic, and combined diets. Goossens and Jornayvaz [
According to Mikhail et al. [
These models allow researchers to control,
In conclusion, the findings of this review show that the diet is one of the factors that predisposes to the appearance of NAFLD and that the studies presented a wide variety of designs, with the DHC being the most frequent diets in studies with experimental models of NAFLD. These reinforce that animal diet models are able to mimic the pathophysiological characteristics of NAFLD and are still widely used in research, mainly related to the testing of compounds that interfere with the progression of the disease.
The data used to support the findings of this study are included within the article.
The authors declare that they have no conflicts of interest.