Antioxidative Self-Assembling Nanoparticles Attenuate the Development of Steatohepatitis and Inhibit Hepatocarcinogenesis in Mice
Takahisa Watahiki,
Kosuke Okada,
Ikuru Miura,
Keii To,
Seiya Tanaka,
Eiji Warabi,
Naomi Kanno,
Kenji Yamagata,
Naohiro Gotoh,
Hideo Suzuki,
Shunichi Ariizumi,
Kiichiro Tsuchiya,
Yukio Nagasaki,
Junichi Shoda
Affiliations
Takahisa Watahiki
Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Kosuke Okada
Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Ikuru Miura
Doctoral Program in Sports Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Keii To
Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Seiya Tanaka
Department of Food Science and Technology, Tokyo University of Marine Science and Technology, 4-5-7 Konan, Minato-ku, Tokyo 108-8477, Japan
Eiji Warabi
Division of Biomedical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Naomi Kanno
Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Kenji Yamagata
Department of Oral and Maxillofacial Surgery, Institute of Clinical Medicine, Faculty of Medicine, University of Tsukuba 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Naohiro Gotoh
Department of Food Science and Technology, Tokyo University of Marine Science and Technology, 4-5-7 Konan, Minato-ku, Tokyo 108-8477, Japan
Hideo Suzuki
Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Shunichi Ariizumi
Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Kiichiro Tsuchiya
Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Yukio Nagasaki
Faculty of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8573, Japan
Junichi Shoda
Division of Medical Sciences, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
Oxidative stress (OS) contributes to nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. We investigated whether antioxidative self-assembling nanoparticles (SMAPoTN) could reduce the development of NASH and hepatocellular carcinoma (HCC) in p62/Sqstm1 and Nrf2 double knockout (DKO) mice and studied protective mechanisms. We measured disease development in male DKO mice fed a normal chow (NASH model) or a 60% high-fat diet (HFD; HCC model) with or without SMAPoTN administration for 26 weeks. SMAPoTN inhibited liver fibrosis in both groups and prevented HCC development (0% vs. 33%, p TN reduced OS, inflammatory cytokine signaling, and liver fibrosis. RNA-sequencing revealed that SMAPoTN decreased endoplasmic reticulum stress signaling genes in both groups, HCC driver genes, and cancer pathway genes, especially PI3K-AKT in the HFD groups. In the SMAPoTN treatment HFD group, serum lipopolysaccharide levels and liver lipopolysaccharide-binding protein expression were significantly lower compared with those in the nontreatment group. SMAPoTN improved the α-diversity of gut microbiota, and changed the microbiota composition. Oral SMAPoTN administration attenuated NASH development and suppressed hepatocarcinogenesis in DKO mice by improving endoplasmic reticulum stress in the liver and intestinal microbiota. SMAPoTN may be a new therapeutic option for NASH subjects and those with a high HCC risk.
