Itih3, also known as inter-trypsin inhibitor heavy chain 3, is a hepatokine that may play significant roles in multiple biological processes. It has been associated with the regulation of mitochondrial bioenergetics and de novo lipogenesis, and is involved in extracellular matrix stabilization [1,3].

In animal and cell culture models, hepatic Itih3 overexpression lowered liver triglyceride and lipid droplet accumulation, while Itih3 knockdown in mice increased liver triglyceride in two independent non-alcoholic fatty liver disease (NAFLD) models. Mechanistically, Itih3 reduced mitochondrial respiration, which in turn decreased liver triglycerides via downregulated de novo lipogenesis. This was accompanied by increased STAT1 signaling and Stat3 expression, both protective against NAFLD/NASH [1]. In ovarian carcinoma, downregulation of Itih3 contributed to cisplatin-based chemotherapy resistance via the Bcl-2 mediated anti-apoptosis signaling pathway [2].

In conclusion, Itih3 has essential functions in regulating lipid metabolism as shown by in vivo studies in mouse models, especially in the context of NAFLD. Its role in chemotherapy resistance in ovarian cancer also highlights its importance in disease-related research. These findings from gene-based model studies contribute to understanding the biological functions of Itih3 and its potential as a biomarker or treatment target in relevant diseases.

References:

1. Talari, Noble Kumar, Mattam, Ushodaya, Kaminska, Dorota, Pihlajamäki, Jussi, Chella Krishnan, Karthickeyan. 2024. Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis. In iScience, 27, 109709. doi:10.1016/j.isci.2024.109709. https://pubmed.ncbi.nlm.nih.gov/38689636/

2. Liu, Yingzhao, Shi, Lijun, Yuan, Cunzhong, Yao, Desheng, Wang, Qi. 2022. Downregulation of ITIH3 contributes to cisplatin-based chemotherapy resistance in ovarian carcinoma via the Bcl-2 mediated anti-apoptosis signaling pathway. In Oncology letters, 25, 61. doi:10.3892/ol.2022.13646. https://pubmed.ncbi.nlm.nih.gov/36644154/

3. Miyake, Yoshihiro, Tanaka, Keiko, Arakawa, Masashi. 2018. ITIH3 and ITIH4 polymorphisms and depressive symptoms during pregnancy in Japan: the Kyushu Okinawa Maternal and Child Health Study. In Journal of neural transmission (Vienna, Austria : 1996), 125, 1503-1509. doi:10.1007/s00702-018-1905-1. https://pubmed.ncbi.nlm.nih.gov/29992445/