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

Miyagawa, Sawa Horie, Takahiro Nishino, Tomohiro Koyama, Satoshi Watanabe, Toshimitsu Baba, Osamu Yamasaki, Tomohiro Sowa, Naoya Otani, Chiharu Matsushita, Kazuki Kojima, Hidenori Kimura, Masahiro Nakashima, Yasuhiro Obika, Satoshi Kasahara, Yuuya Kotera, Jun Oka, Kozo Fujita, Ryo Sasaki, Takashi Takemiya, Akihiro Hasegawa, Koji Kimura, Takeshi Ono, Koh 京都大学 DOI:10.26508/lsa.202301902

2023.08

概要

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.

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参考文献

The data that support the findings of this study are available from

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Supplementary Information

Supplementary Information is available at https://doi.org/10.26508/lsa.

202301902

Acknowledgements

This work was supported by the Ministry of Education, Culture, Sports,

Science and Technology (MEXT) and Japan Society for the Promotion of

Science (JSPS) KAKENHI Grants 17K09860 and 20K08904 (to T Horie), and

17H04177, 17H05599, and 20H03675 (to K Ono), as well as a grant from the Cell

Science Research Foundation (to T Horie). This research was also supported

by AMED under Grant Number 21ym0126013h0001 (to K Ono).

Author Contributions

S Miyagawa: data curation, formal analysis, and investigation.

T Horie: conceptualization, data curation, formal analysis, supervision, funding acquisition, investigation, and writing—original

draft.

T Nishino: data curation and formal analysis.

S Koyama: data curation and formal analysis.

T Watanabe: data curation.

O Baba: investigation.

T Yamasaki: data curation, formal analysis, and investigation.

N Sowa: data curation and formal analysis.

C Otani: data curation and investigation.

K Matsushita: data curation and investigation.

H Kojima: data curation, formal analysis, and investigation.

M Kimura: data curation, formal analysis, and investigation.

Y Nakashima: investigation.

S Obika: data curation and methodology.

Y Kasahara: data curation and methodology.

J Kotera: data curation and methodology.

K Oka: data curation and methodology.

R Fujita: data curation and methodology.

T Sasaki: data curation and methodology.

A Takemiya: data curation and methodology.

K Hasegawa: data curation and investigation.

T Kimura: data curation, supervision, and investigation.

K Ono: conceptualization, formal analysis, supervision, funding

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