Inhibition of microRNA-33b in humanized mice ameliorates nonalcoholic steatohepatitis

• DOI: 10.26508/lsa.202301902
• Publication Date: 2023-06-15T17:52:05Z
• Authors: Sawa Miyagawa; Takahiro Horie; Tomohiro Nishino; Satoshi Koyama; Toshimitsu Watanabe; Osamu Baba; Tomohiro Yamasaki; Naoya Sowa; Chiharu Otani; Kazuki Matsushita; Hidenori Kojima; Masahiro Kimura; Yasuhiro Nakashima; Satoshi Obika; Yuuya Kasahara; Jun Kotera; Kozo Oka; Ryo Fujita; Takashi Sasaki; Akihiro Takemiya; Koji Hasegawa; Takeshi Kimura; Koh Ono
• Keywords: Mice; MicroRNAs; Cholesterol; Non-alcoholic Fatty Liver Disease; Liver Neoplasms; Humans; Animals; Antagomirs; Research Articles; 3. Good health; Transcription Factors

Nonalcoholic steatohepatitis (NASH) can lead to cirrhosis and hepatocellular carcinoma in their advanced stages; however, there are currently no approved therapies. Here, we show that microRNA (miR)-33b in hepatocytes is critical for the development of NASH. miR-33b is located in the intron of sterol regulatory element–binding transcription factor 1 and is abundantly expressed in humans, but absent in rodents. miR-33b knock-in (KI) mice, which have a miR-33b sequence in the same intron of sterol regulatory element–binding transcription factor 1 as humans and express miR-33b similar to humans, exhibit NASH under high-fat diet feeding. This condition is ameliorated by hepatocyte-specific miR-33b deficiency but unaffected by macrophage-specific miR-33b deficiency. Anti-miR-33b oligonucleotide improves the phenotype of NASH in miR-33b KI mice fed a Gubra Amylin NASH diet, which induces miR-33b and worsens NASH more than a high-fat diet. Anti-miR-33b treatment reduces hepatic free cholesterol and triglyceride accumulation through up-regulation of the lipid metabolism–related target genes. Furthermore, it decreases the expression of fibrosis marker genes in cultured hepatic stellate cells. Thus, inhibition of miR-33b using nucleic acid medicine is a promising treatment for NASH.