Brain-derived neurotrophic factor knock-out mice develop non-alcoholic steatohepatitis

While brain-derived neurotrophic factor (BDNF), which is a growth factor associated with cognitive improvement and the alleviation of depression symptoms, is known to regulate food intake and body weight, the role of BDNF in peripheral disease is not fully understood. Here, we show that reduced BDNF expression is associated with weight gain and the chronic liver disease nonalcoholic steatohepatitis (NASH). At 10 months of age, BDNF-heterozygous (BDNF+/-) mice develop symptoms of NASH: centrilobular/perivenular steatosis, lobular inflammation with infiltration of neutrophils, ballooning hepatocytes, and fibrosis of the liver. Obesity and higher serum levels of glucose and insulin—major pathologic features in human NASH—are dramatic. Dying adipocytes are surrounded by macrophages in visceral fat, suggesting that chronic inflammation occurs in peripheral organs. RNA-seq studies of the liver revealed that the most significantly enriched gene ontology term involves fatty acid metabolic processes and the modulation of neutrophil aggregation, pathologies that well characterise NASH. Gene expression analysis by RNA-seq also suggested that the BDNF+/- mice are under oxidative stress, as indicated by alterations in the expression of the cytochrome P450 family and a reduction in glutathione S-transferase p, an antioxidant enzyme. Histopathologic phenotypes of NASH were also observed in a knock-in mouse (BDNF+/pro), in which the precursor BDNF is inefficiently converted into the mature form of BDNF. Lastly, as BDNF reduction causes overeating and subsequent obesity, a food restriction study was conducted in BDNF+/pro mice. Pair-fed BDNF+/pro mice developed hepatocellular damage and showed infiltration of inflammatory cells including neutrophils in the liver, despite having body weights and blood parameters that were comparable to controls. Collectively, this is the first report demonstrating that reduced BDNF expression plays a role in the pathogenic mechanism of NASH, which is a hepatic manifestation of metabolic syndrome.

内容要旨・審査要旨・論文本文の公開
本論文は，著者Mayuko Ichimura-Shimizuの学位論文として提出され，学位審査・授与の対象となっている。

This is the peer reviewed version of the following article: Ichimura-Shimizu, M., Kojima, M., Suzuki, S., Miyata, M., Osaki, Y., Matsui, K., Mizui, T., Tsuneyama, K., (2023), Brain-derived neurotrophic factor knock-out mice develop non-alcoholic steatohepatitis. The Journal of Pathology, 261, 4, 465-476., which has been published in final form at https://doi.org/10.1002/path.6204. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.