Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

Fang, Tingyu; Wang, Hua; Pan, Xiaoyue; Little, Peter J.; Xu, Suowen; Weng, Jianping

doi:10.7150/ijbs.65044

Cited by 39 publications

(15 citation statements)

References 190 publications

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“…Based on previous studies, there is no unified method for establishing MAFLD mouse models 34 , 35 . In many studies, ApoE -/- mice were fed with HFD at approximately 8-12 weeks 36 , 37 . All MAFLD mouse models were testified by Oil red O staining and other metabolic-associated tests to prove successful modeling.…”

Section: Discussionmentioning

confidence: 99%

The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD

Jiang,

Luo,

Cao

et al. 2024

Int. J. Biol. Sci.

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Metabolic-associated fatty liver disease (MAFLD) is a globally prevalent chronic hepatic disease. Previous studies have indicated that the activation of the signal transducer and activator of transcription3 (STAT3) plays a vital role in MAFLD progression at the very beginning. However, the specific association between STAT3 and abnormal hepatic metabolism remains unclear. In this study, activated inflammation was observed to induce abnormal glucolipid metabolic disorders in the hepatic tissues of high-fat diet (HFD)-fed ApoE -/- mice. Furthermore, we found that the activation of STAT3 induced by HFD might function as a transcriptional factor to suppress the expression of VAV3, which might participate in intracellular glucolipid metabolism and the regulation of glucose transporter 4 (GLUT4) storage vesicle traffic in the development of MAFLD both in vitro and in vivo . We verified that VAV3 deficiency could retard the GLUT4 membrane translocation and impair the glucose homeostasis. Additionally, VAV3 participates in cholesterol metabolism in hepatocytes, eventually resulting in the accumulation of intracellular cholesterol. Moreover, rAAV8-TBG-VAV3 was conducted to restore the expression of VAV3 in HFD-fed ApoE -/- mice. VAV3 overexpression was observed to improve glucose homeostasis as well as attenuate hepatic cholesterol accumulation in vivo . In conclusion, the STAT3/VAV3 signaling pathway might play a significant role in MAFLD by regulating glucose and cholesterol metabolism, and VAV3 might be a potential therapeutic strategy which could consequently ameliorate MAFLD.

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Section: Discussionmentioning

confidence: 99%

The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD

Jiang,

Luo,

Cao

et al. 2024

Int. J. Biol. Sci.

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“…The I-WD mice exhibited an increase in the glucose tolerance test curve, highlighting the development of glucose intolerance, and an increase in total cholesterol, LDL, HDL, and TG levels, indicating dyslipidemia [ 36 ]. In the liver, the I-WD mice exhibited hepatomegaly development, significant steatosis associated with hepatocyte ballooning, and type 3 collagen gene expression, which are distinctive of NAFLD development [ 35 , 37 ]. This pattern of repetitive weight loss and regain associated with the development of metabolic complications is characteristic of weight cycling [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Changes in Macronutrients during Dieting Lead to Weight Cycling and Metabolic Complications in Mouse Model

Charlot,

Bringolf,

Debrut

et al. 2024

Nutrients

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Weight cycling is a major challenge in obesity management. Caloric restriction is known to promote this phenomenon, but the impact of macronutrient changes during dieting remains unclear. This study aimed to determine the role of macronutrient changes in weight maintenance without caloric restriction by alternating between two hypercaloric diets: a high-carbohydrate, high-fat Western diet (WD) and a low-carbohydrate, high-fat diet (LCHDF). Obesity was induced in 8-week-old C57BL/6 male mice by 10 weeks of WD feeding. Then, the mice were subjected to 12 weeks of LCHFD interspersed with WD (I-WD), 3 periods of 2-week LCHFD followed by 2 periods of 3-week WD, or 12 weeks of continuous WD (C-WD). C-WD and I-WD mice were compared to standard diet (SD) mice. In the I-WD group, each LCHFD period decreased weight gain, but mice regained weight after WD resumption. I-WD mice exhibited obesity, dyslipidemia, and glucose intolerance, similarly to the C-WD mice. I-WD mice also developed nonalcoholic steatohepatitis, associated with an increase in type-III collagen gene expression and a decrease in FGF21 protein levels, in comparison with SD. I-WD mice developed weight cycling despite maintaining a high caloric consumption, suggesting that changes in macronutrients during dieting are also a trigger of weight regain.

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“…This increase in necroptosis was associated with an increase in markers of inflammation in the liver. Because inflammation plays a role in chronic liver disease [ 35 ] and chronic liver disease increases with age, we measured the impact of overexpressing either Ripk3 or Mlkl on steatosis and fibrosis in the old mice. We found that the age-related increase steatosis and fibrosis was significantly increased in the old hRipk 3-KI and hMlkl -KI mice.…”

Section: Discussionmentioning

confidence: 99%

Characterization of novel mouse models to study the role of necroptosis in aging and age-related diseases

Selvarani,

Van Michelle Nguyen,

Thadathil

et al. 2023

GeroScience

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To study the impact of necroptosis-induced chronic inflammation on age-related diseases and aging, two knockin mouse models (Ripk3-KI and Mlkl-KI) were generated that overexpress two genes involved in necroptosis (Ripk3 or Mlkl) when crossed to Cre transgenic mice. Crossing Ripk3-KI or Mlkl-KI mice to albumin-Cre transgenic mice produced hepatocyte specific hRipk3-KI or hMlkl-KI mice, which express the two transgenes only in the liver. Ripk3 and Mlkl proteins were overexpressed 10- and fourfold, respectively, in the livers of the hRipk3-KI or hMlkl-KI mice. Treating young (2-month) hRipk3-KI or hMlkl-KI mice with carbon tetrachloride (CCl4), a chemical inducer of oxidative stress, resulted in increased necroptosis (Mlkl-oligomers) and inflammation in the liver compared to control mice receiving CCl4. Mlkl-oligomerization also was significantly increased in old (18-month) hRipk3-KI and hMlkl-KI mice compared to old control (Cre negative, Ripk3-KI and Mlkl-KI) mice. The increase in necroptosis was associated with an increase in inflammation, e.g., inflammatory cytokines (TNFα, IL-6) and macrophage markers (F4/80, CD68). Importantly, steatosis (triglycerides) and fibrosis (e.g., picrosirius red staining, hydroxyproline levels, and transcripts for TGFβ, Col1α1, and Col3α1) that increase with age were significantly higher in the livers of the old hRipk3-KI or hMlkl-KI mice compared to old control mice. In addition, markers of cellular senescence were significantly increased in the livers of the old hRipk3-KI and hMlkl-KI mice. Thus, the first mouse models have been developed that allow researchers to study the impact of inducing necroptosis in specific cells/tissues on chronic inflammation in aging and age-related diseases.

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Mouse models of nonalcoholic fatty liver disease (NAFLD): pathomechanisms and pharmacotherapies

Cited by 39 publications

References 190 publications

The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD

The role of STAT3/VAV3 in glucolipid metabolism during the development of HFD-induced MAFLD

Changes in Macronutrients during Dieting Lead to Weight Cycling and Metabolic Complications in Mouse Model

Characterization of novel mouse models to study the role of necroptosis in aging and age-related diseases

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