5 KCs differ in their morphological characteristics, physiological functions, and population density in the liver acinus. Those localized in the periportal zone express the scavenger receptor CD163, also described as ED2 antigen, and exhibit higher activity of phagocytosis and lysosomal protease activity as well as greater release more biological active mediators, such as cytokines, than KCs located in the perivenous and midzonal areas.6 By contrast, glycosylated FK506 in vitro transmembrane protein CD68 (ED1) is detected in all KCs regardless of acinar location. Increased expression

of CD68-positive KCs is related to the histological severity of the livers of patients with NAFLD. In addition, aggregates of enlarged KCs exist in perivenular regions of the livers of patients with NASH compared with the diffuse distribution seen in simple steatosis (SS).7 Absent KCs or impaired KC function may be associated with harmful effects. Resultant impaired clearance of bacterial products, lipopolysaccharides (LPS), endotoxins, and other dangerous molecules may accelerate pathogenesis of liver diseases. Depletion of KCs by gadolinium chloride (GdCl3) or clodronate liposomes has been reported to shift the distribution of phagocytosis and alter the balance of cytokines release, thereby reflecting

the functional complexity and phenotypic plasticity of Acalabrutinib molecular weight KCs.8 In contrast, when ED2-positive KCs are selectively depleted by GdCl3 or clodronate, liver diseases GABA Receptor induced by alcohol, carbon tetrachloride, thioacetamide, and ischemia/reperfusion are remarkably attenuated. In addition, deletion of ED2-positive KCs by GdCl3 or clodronate attenuates proinflammatory and profibrogenic cytokine release, thereby protecting fatty livers from progression to NASH. In summary, these results

indicate that ED2-positive KCs are involved in the progression of various kinds of liver disease, including NASH. Most LPS in the body is produced in the gastrointestinal (GI) tract and enters the liver through the portal vein. The liver is the final barrier to prevent GI bacteria and LPS from entering the systemic circulation. Because of the location of KCs in the liver sinusoids, which drain the GI tract through the portal vein, KCs are chronically exposed to higher concentrations of LPS than are peripheral macrophages. Therefore, impaired phagocytotic function of KCs leads to elevation of circulating LPS in experimental models of NASH.9 Elevation of circulating LPS from the GI tract is also considered important in the pathogenesis for NASH because control of bacterial overgrowth in the GI tract by administration of probiotics led to improvement of NASH.