Progress in the Study of Animal Models of Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as an alternative term to NAFLD. MASLD is a globally recognized chronic liver disease that poses significant health concerns and is frequently associated with obesity, insulin resistance, and hyperlipidemia. To better understand its pathogenesis and to develop effective treatments, it is essential to establish suitable animal models. Therefore, attempts have been made to establish modelling approaches that are highly similar to human diet, physiology, and pathology to better replicate disease progression. Here, we reviewed the pathogenesis of MASLD disease and summarised the used animal models of MASLD in the last 7 years through the PubMed database. In addition, we have summarised the commonly used animal models of MASLD and describe the advantages and disadvantages of various models of MASLD induction, including genetic models, diet, and chemically induced models, to provide directions for research on the pathogenesis and treatment of MASLD.

Keywords: MASLD; animal model; pathology; physiology.

Figure 1

Histological lesions of hepatic steatosis in nonhuman primates and ApoE^-/- mice. Panels (A,B) show hematoxylin and eosin (HE) staining results of fatty liver induced by a high-fat diet in nonhuman primates and ApoE^-/- mice, respectively. The arrow points to the histological lesion of typical liver steatosis with vesicular fat accumulation. Data were obtained from the results of experiments performed in our laboratory (unpublished data).

Figure 2

Hepatic free fatty acid (FFA) synthesis, metabolic processes, and related major genes. Fatty liver is formed mainly by an imbalance between the increase in fatty acids (red arrows) and their metabolism (green arrows). Glucose and insulin activate the transcription factor sterol regulatory binding protein (SREBP-1C) and the transcription factor carbohydrate response element binding protein (ChREBP), respectively, to synthesize triglycerides (TG) and produce FFA. Hepatic FFAs can also be derived from the diet and circulating fatty acids. In the liver, FFAs are stored as triglycerides (TG) to form lipid droplets or exported as very low-density lipoproteins (VLDL). Excess FFAs undergo beta-oxidation in mitochondria or degradation in lysosomes for reuse. FFA, free fatty acid; DNL, De novo lipogenesis; ChREBP, carbohydrate response element binding protein; SREBP-1C, sterol regulatory element binding protein 1-C; ACC, acetyl coenzyme A carboxylase; FAS, fatty acid synthase; SCD1, stearoyl coenzyme A desaturase 1; ELOVL, extra-long-chain fatty acid extension; DAG, diacyl triglyceride; DGAT, diester acylglycerol acyltransferase; HSL, hormone-sensitive lipase; ATGL, adipose triglyceride lipase; CD36, lipid transporter protein; LDLR, low density lipoprotein receptor; ACC, acetyl coenzyme A carboxylase; FFA, free fatty acid; TG, triglyceride; VLDL, very-low-density lipoprotein; MTTP, microsomal triglyceride transfer protein; ApoB100, apolipoprotein B100; ROS, reactive oxygen species; ACSL1, long-chain acyl coenzyme A synthase 1; CPT1, carnitine palmitoyltransferase 1; AOX, fatty acyl coenzyme A oxidase; CYP2E1, cytochrome P4502E1.

Figure 3

Number of animal models used in the last seven years. There were 519 articles in 2018, 744 articles in 2019, 461 articles in 2020, 425 articles in 2021, 508 articles in 2022, 737 articles in 2023, and 491 articles in 2024. Among the 3885 articles, there were 2949 mouse models, 842 rat models, 52 zebrafish models, 23 rabbit models, 13 pig models, five chicken models, and one sheep model.

Figure 4

Summary of mouse gene knockout models and MASLD induction methods. The C57BL/6J and C57BL/6 mouse background is predominantly used, including knockout models such as ob/ob, ApoE^-/-, Ldlr^-/-, db/db, and foz/foz. For MASLD induction, HFD is most commonly used, followed by the MCD diet, high fat/high cholesterol diet, high-fat/high-sucrose or fructose diet, high fat/high fructose/high cholesterol, high sucrose or high fructose diets.