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  • br Animal models of NAFLD Human research

    2024-04-03


    Animal models of NAFLD Human research has greatly shaped our understanding of non-alcoholic fatty liver disease, but several limitations exist in studying the disease processes in humans, such as variations in environmental exposure, pre-existing genetic risk factors, racial and ethnic differences in disease presentation, and need for multiple invasive procedures among others. Research in animals enables us to circumvent several of these issues. An ideal animal model for NAFLD must replicate human disease closely, by exhibiting fatty liver associated with inflammation in an environment of nutrient excess, preferably associated with features of metabolic syndrome such as obesity and insulin resistance. The animal model should be easy to breed and maintain in the lab environment in addition to achieving the desired disease phenotype in a reasonable timeframe. Several animal models are available to study NAFLD; each one presenting both advantages and limitations. Currently, both mice and pigs have been used in NAFLD research, though rodent studies are far more common. NAFLD occurs naturally in mice, but it can also be induced more reproducibly through genetic alterations/mutations. Alternatively, NAFLD can be induced in animals by feeding mice diets with high fat or carbohydrate content, such that 60% of caloric count is derived from fat alone and/or cholesterol or simple carbohydrates. Simple carbohydrates, such as glucose and fructose generate abundant levels of glycerol-3-phosphate, which can be used in triglyceride synthesis. Moreover, as fructokinase is not regulated by insulin, excessive fructose can lead to unregulated production of acetyl-Co-A, which is in turn converted to triglycerides. Diets deficient in essential nutrients can also result in fatty liver. Listed in Table 2 are the various rodent models currently used to study NAFLD and their advantages and limitations. Ossabaw pigs, a breed of pig originally found on an island off the state of Georgia in the United States, acquired a “thrifty gene” to adapt to seasonable variability of food availability. These pigs develop steatosis and steatohepatitis when fed a diet high in fats. However, they are not widely used in research due to cumbersome nature of breeding and maintaining these animals in laboratory setting. In light of the limitations of rodent and pig models of NAFLD, there is a need for new animal models that address these shortcomings. Zebrafish is being explored as a potential animal model to study NAFLD. The similarity of zebrafish hepatopancreaticobiliary anatomy to humans and presence of orthologues to most human genes in zebrafish, including synteny make zebrafish an attractive animal model for hepatopancreaticobiliary disease. In addition, genetic tractability and transgenic feasibility allow for development of desired animal models with Myriocin of interested study pathways. Rapid external development of transparent zebrafish embryo allows for study of effect of gene expression patterns on embryonic development in a time efficient manner. All the above features lend zebrafish to study of hepatopancreaticobiliary disease.
    Conclusion In this review, we summarize the putative role of oxidative stress and ER stress in the development of nonalcoholic steatohepatitis and identify the 12-LOX as an under-recognized, albeit important, contributor to the pathogenesis of NAFLD. It is as yet unclear whether current approaches to therapy (weight loss, thiazolidinediones, GLP-1 receptor agonists, FXR agonists) might operate in part through the alteration of 12-LOX activity. As such, recently developed inhibitors of 12-LOX) may represent a novel approach to the treatment and/or prevention of NAFLD, and such inhibitors may augment current approaches to treatment.
    Introduction The 12- lipoxygenase (LO) pathway is a potentially promising target to reduce AT inflammation, islet dysfunction and insulin resistance [[1], [2]]. The relevance of the pathway in insulin resistance is illustrated by several proof-of-concept studies in rodents. 12/15LO knockout mice are protected from insulin resistance in diet-induced obesity and 12/15LO expression is required for initiation of insulin resistance in obesity [[3], [4], [5], [6]]. 12/15LO expression is highly upregulated in adipocytes of high fat fed mice and its deletion protects mice from developing increases in pro-inflammatory cytokines, maintains normal adiponectin levels and fully maintains glycemic control compared to wild type mice fed the same diet [7]. Recent data indicate that direct addition of 12/15LO lipid products to fully differentiated 3T3L1 adipocytes leads to upregulation of pro-inflammatory cytokines and significant reduction of adiponectin [8]. Our group has demonstrated activation of the 12/15 and 5-LO pathways in AT, SVF and adipocytes in obese Zucker rats [9]. Importantly, studies from our laboratory showed that 12LO is upregulated in cytokine-treated human islets and that direct addition of 12-HETE leads to β cell dysfunction and loss of viability [[10], [11]]. An important aspect of 12 and 15- lipoxygenase pathways is production of pro-resolving mediators of inflammation from ω3 fatty acids such as DHA and EPA [[12], [13]]. These anti-inflammatory metabolites were carefully characterized and while their roles in resolving acute inflammation is well established their roles in chronic inflammatory conditions such as obesity and diabetes is just beginning to emerge [[14], [15]]. Also, importantly, only the 12(S)- and 15(S)- isomers are known to exert biological activity, while the (R) isomers are non-enzymatically generated primarily ex-vivo and lack biological activity. Therefore, characterization of both the pro- and anti-inflammatory biologically active metabolites of lipoxygenase pathways is of prime importance.