Ikumi Sato1, Shusei Yamamoto1,2, Mai Kakimoto1, Moe Fujii1, Koki Honma1, Shota Kumazaki1, Mami Matsui3, Hinako Nakayama1, Sora Kirihara1, Shang Ran1, Shinichi Usui4, Ryoko Shinohata2, Kazuya Kitamori5, Satoshi Hirohata2, Shogo Watanabe6. 1. Department of Medical Technology, Graduate School of Health Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan. 2. Academic Field of Health Science, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan. 3. Department of Medical Technology, Faculty of Health Sciences, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan. 4. Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, 86, Nishi-machi, Yonago-shi, Tottori, 683-8503, Japan. 5. Collage of Human Life and Environment, Kinjo Gakuin University, 2-1723, Omori, Moriyama-ku, Nagoya-shi, Aichi, 463-8521, Japan. 6. Academic Field of Health Science, Okayama University, 2-5-1, Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan. watanabe1224@okayama-u.ac.jp.
Abstract
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.
BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive subtype of non-alcoholic fatty liver disease (NAFLD) that is closely related to cardiovascular disease (CVD). Nitric oxide (NO) plays a critical role in the control of various biological processes. Dysfunction of the NO signaling pathway is associated with various diseases such as atherosclerosis, vascular inflammatory disease, and diabetes. Recently, it has been reported that NO is related to lipid and cholesterol metabolism. Chronic NO synthase (NOS) inhibition accelerates NAFLD by increasing hepatic lipid deposition. However, the detailed relationship between NO and abnormal lipid and cholesterol metabolism in NAFLD/NASH has not been completely explained. We aimed to determine the effects of NOS inhibition by N omega-nitro-L-arginine methyl ester hydrochloride (L-NAME), a NOS inhibitor, on NASH and CVD via lipid and cholesterol metabolism. METHODS: Stroke-prone spontaneously hypertensive rats were fed a high-fat and high-cholesterol diet for 8 weeks and administered L-NAME for the last 2 weeks. Following blood and tissue sampling, biochemical analysis, histopathological staining, quantitative RT-PCR analysis, and western blotting were performed. RESULTS: L-NAME markedly increased hepatic triglyceride (TG) and cholesterol levels by promoting TG synthesis and cholesterol absorption from the diet. L-NAME increased the mRNA levels of inflammatory markers and fibrotic areas in the liver. Cholesterol secretion from the liver was promoted in rats administered L-NAME, which increased serum cholesterol. L-NAME significantly increased the level of oxidative stress marker and lipid deposition in the arteries. CONCLUSIONS: NOS inhibition simultaneously aggravates NASH and atherosclerosis via hepatic lipid and cholesterol metabolism.
Authors: Christopher D Williams; Joel Stengel; Michael I Asike; Dawn M Torres; Janet Shaw; Maricela Contreras; Cristy L Landt; Stephen A Harrison Journal: Gastroenterology Date: 2010-09-19 Impact factor: 22.682
Authors: Ryan D Sheldon; Jaume Padilla; Nathan T Jenkins; M Harold Laughlin; R Scott Rector Journal: Am J Physiol Gastrointest Liver Physiol Date: 2015-01-08 Impact factor: 4.052