Uno Kinuko, Miyajima Katsuhiro, Toma Marika, Suzuki-Kemuriyama Noriko, Nakae Dai
Department of Food and Nutritional Science, Graduate School of Agriculture, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan.
Department of Nutritional Science and Food Safety, Faculty of Applied Biosciences, Tokyo University of Agriculture, 1-1-1 Sakura-ga-Oka, Setagaya, Tokyo 156-8502, Japan.
J Toxicol Pathol. 2022 Apr;35(2):149-157. doi: 10.1293/tox.2021-0069. Epub 2021 Dec 6.
Nonalcoholic steatohepatitis is a lifestyle-related disease and an increasing threat worldwide. Hepatic fibrosis, which results from chronic hepatic diseases including nonalcoholic steatohepatitis, is closely correlated with mortality among hepatic lesions, such as steatosis and inflammation. Thus, it is important to identify factors that can serve as diagnostic and therapeutic targets for hepatic fibrosis. In this study, we examined the function of CD44 in the development of hepatic fibrosis in choline-deficient, methionine-lowered, L-amino-acid diet-fed rats, especially with respect to the proliferation of bile duct epithelium. Male Fischer 344 rats were fed a choline-deficient, methionine-lowered, L-amino-acid diet for 2, 4, 13, or 26 weeks. This diet decreased the body weight; increased the levels of serum parameters indicating liver injury, such as aspartate and alanine aminotransferase; upregulated inflammation- and fibrosis-related gene expression in the liver; and resulted in the development of hepatic lesions, including fatty changes in hepatocytes, inflammatory cell infiltration, and fibrosis. Hepatic hyaluronan was synthesized and deposited in the liver tissue. The expression of both CD44 mRNA and protein was significantly increased throughout the experimental period. CD44 protein was observed in some of the bile duct epithelium, around which hyaluronic acid was deposited, and these bile duct lesions were concordant with the area of hepatic fibrosis. Thus, CD44 expressed in the bile duct epithelium may be a target for controlling nonalcoholic steatohepatitis-related hepatic fibrosis.
非酒精性脂肪性肝炎是一种与生活方式相关的疾病，在全球范围内构成日益严重的威胁。肝纤维化由包括非酒精性脂肪性肝炎在内的慢性肝病引起，与肝损伤（如脂肪变性和炎症）中的死亡率密切相关。因此，识别可作为肝纤维化诊断和治疗靶点的因素非常重要。在本研究中，我们研究了CD44在胆碱缺乏、蛋氨酸降低、L-氨基酸饮食喂养的大鼠肝纤维化发展中的作用，特别是关于胆管上皮细胞的增殖。雄性Fischer 344大鼠喂食胆碱缺乏、蛋氨酸降低、L-氨基酸饮食2、4、13或26周。这种饮食降低了体重；增加了表明肝损伤的血清参数水平，如天冬氨酸和丙氨酸转氨酶；上调了肝脏中炎症和纤维化相关基因的表达；并导致了肝脏病变的发展，包括肝细胞脂肪变性、炎性细胞浸润和纤维化。肝透明质酸在肝组织中合成并沉积。在整个实验期间，CD44 mRNA和蛋白的表达均显著增加。在一些胆管上皮中观察到CD44蛋白，其周围有透明质酸沉积，并且这些胆管病变与肝纤维化区域一致。因此，胆管上皮中表达的CD44可能是控制非酒精性脂肪性肝炎相关肝纤维化的靶点。
