BMS777607 sale br Animal models of NASH The human NAS system

Animal models of NASH The human NAS system (see above) is largely reproducible in NAFLD mouse models [37] and, therefore, has been increasingly applied in the preclinical assessment of liver histological responses to test compounds. In general, the NAS system is well suited for this purpose, although there is not a complete overlap in NASH pathology between humans and rodents. For example, distinct hepatocyte ballooning is often absent or marginal in rodent NAFLD/NASH models [37] and, therefore, composite NAS in experimental NASH models is largely determined by the grade of hepatic steatosis and inflammation. This also indicates that currently available mouse models of NASH are not optimal for evaluating drug effects on hepatocyte degeneration and, thus, measures should also include apoptotic markers. Murine models constitute the bulk of research in preclinical NASH pathology, and a subset of mouse models exhibits good clinical translatability. Thus, here we discuss selected mouse models to demonstrate the diversity of the attempts to establish in vivo models that recapitulate the etiology, natural history, histopathology, and disease progression. We focus on murine NASH models used for test of pharmacological agents, as listed in Table 2, Table 3, Table 4.
Concluding remarks
Acknowledgments
Introduction Bile acids (BAs) have for a long time been viewed as detergents able to solubilize cholesterol, fatty acids, and liposoluble vitamins, thus facilitating the digestion, transportation, and gastrointestinal BMS777607 sale of nutrients. BAs have also been shown to be involved in a large variety of cellular processes. Some recent discoveries have unveiled novel actions of BAs as signaling hormones endowed with a wide array of endocrine functions. In 1999, three research groups independently identified BAs as endogenous ligands for a nuclear receptor, the farnesoid X receptor (FXR) [1], [2], [3]. In early 2000, two research groups discovered that a novel class A G-protein-coupled receptor (GPCR), TGR5 (also known as GPBAR1, GPCR19, GPR131, BG37, M-BAR, Rup 43), can be activated by BAs [4], [5]. Highly expressed in the liver, intestine, kidney, adrenal glands, and adipose tissue, FXR is a master regulator of the synthesis and pleiotropic actions of endogenous BAs [6]. Activation of FXR by BAs or synthetic FXR agonists lowers plasma triglycerides by a mechanism involving repression of hepatic sterol regulatory element binding protein-1c (SREBP-1c) expression and the modulation of glucose-dependent lipogenic genes. Furthermore, FXR controls lipid and glucose metabolism through regulation of gluconeogenesis and glycogenolysis in the liver and through regulation of peripheral insulin sensitivity in striated muscle and adipose tissue [7], [8], [9]. Similar to effects in the liver, FXR agonists modulate lipid metabolism and promote anti-inflammatory and antifibrotic effects in the kidney, suggesting a potential use of FXR agonists to treat diabetic nephropathy and other fibrotic renal diseases [10]. TGR5 is expressed in brown adipose tissue, muscle, liver, intestine, gallbladder [11], and selected areas of the central nervous system [5]. TGR5 activation in intestinal enteroendocrine L cells stimulates secretion of the incretin glucagon-like peptide-1 (GLP-1) [12]. Activation of GLP-1 receptors by derivatives of exendin-4 or enhancement of GLP-1 half-life by dipeptidyl peptidase-4 inhibitors is clinically well-established therapeutic approaches for the treatment of type 2 diabetes [13]. By augmenting GLP-1 activity, these agents improve glycemic control in diabetic patients through increase of glucose-dependent insulin secretion and reduction of glucagon production. Treatment of mice fed a high fat diet with the TGR5 agonist oleanolic acid resulted in lower serum glucose and insulin levels and enhanced glucose tolerance [14]. In addition, administration of BAs to mice increased energy expenditure in brown adipose tissue, preventing obesity and insulin resistance via TGR5-mediated cAMP-dependent induction of type 2 iodothyronine deiodinase (D2), which locally stimulates thyroid hormone-mediated thermogenesis [15].