Higd1a, also known as hypoxia-inducible gene domain family member 1A, is a mitochondrial inner membrane protein. It plays crucial roles in regulating metabolic homeostasis, with functions in anti-apoptosis and promoting cellular survival under hypoxic conditions. It is associated with pathways like those related to mitochondrial respiration, ROS regulation, and DNA damage response, and is of great biological importance in various tissues [3].

In diet-induced obese mice, knockdown of Higd1a in the liver impaired exercise-mediated alleviation of hepatic steatosis, liver injury, and inflammation. This indicates that Higd1a is essential for exercise-related improvement in non-alcoholic fatty liver disease (NAFLD). Deficiency of Higd1a in hepatocytes promoted free fatty acids (FFAs)-induced apoptosis and oxidative stress, activated NLRP3 inflammasome and JNK signaling, and decreased the expression of genes involved in fatty acid oxidation (FAO) [1]. In adipose tissue, HIGD1A knockdown in inguinal and brown fat of mice impaired thermogenesis and made them prone to diet-induced obesity (DIO), as it increased ROS levels, NAD+ consumption, and inhibited SIRT1 activity, thus compromising adipocyte browning [2].

In conclusion, Higd1a is vital for maintaining mitochondrial homeostasis and metabolic health. Gene-knockout (KO) mouse models have revealed its significance in diseases such as NAFLD and DIO. These models help us understand how Higd1a-mediated pathways can be targeted for therapeutic interventions in related metabolic disorders.

References:

1. Zhu, Jie-Ying, Chen, Min, Mu, Wang-Jing, Luo, Hong-Yang, Guo, Liang. 2022. Higd1a facilitates exercise-mediated alleviation of fatty liver in diet-induced obese mice. In Metabolism: clinical and experimental, 134, 155241. doi:10.1016/j.metabol.2022.155241. https://pubmed.ncbi.nlm.nih.gov/35750235/

2. Li, Bai-Yu, Peng, Wan-Qiu, Liu, Yang, Guo, Liang, Tang, Qi-Qun. 2023. HIGD1A links SIRT1 activity to adipose browning by inhibiting the ROS/DNA damage pathway. In Cell reports, 42, 112731. doi:10.1016/j.celrep.2023.112731. https://pubmed.ncbi.nlm.nih.gov/37393616/

3. Zhu, Jie-Ying, Chen, Min, Mu, Wang-Jing, Luo, Hong-Yang, Guo, Liang. 2022. The functional role of Higd1a in mitochondrial homeostasis and in multiple disease processes. In Genes & diseases, 10, 1833-1845. doi:10.1016/j.gendis.2022.03.018. https://pubmed.ncbi.nlm.nih.gov/37492734/