Higd1a, also known as hypoxia-inducible gene domain family member 1A, is a mitochondrial inner membrane protein. It is involved in regulating metabolic homeostasis and plays a crucial role in anti-apoptosis, promoting cellular survival under hypoxic conditions. It also links SIRT1 activity to adipose browning and is a positive regulator of cytochrome c oxidase, which is important for ATP production during mitochondrial oxidative phosphorylation [3,2,4].

In diet-induced obese mice, knockdown of Higd1a in the liver impairs exercise-mediated alleviation of hepatic steatosis, liver injury, and inflammation. Deficiency of Higd1a in hepatocytes promotes free fatty acids-induced apoptosis and oxidative stress, activates NLRP3 inflammasome and JNK signaling, and decreases the expression of genes involved in fatty acid oxidation. Conversely, hepatic overexpression of Higd1a ameliorates fatty liver, liver injury, and inflammation in synergy with exercise [1]. In mice with Higd1a knockdown in inguinal and brown fat, thermogenesis is impaired, and they are prone to diet-induced obesity. Overexpression of Higd1a promotes adipose tissue browning, preventing diet-induced obesity and metabolic disorders [2].

In conclusion, Higd1a is essential for maintaining metabolic homeostasis, especially in processes related to mitochondrial function, fatty acid oxidation, and adipose browning. Gene knockout and overexpression mouse models have revealed its role in non-alcoholic fatty liver disease and diet-induced obesity, providing insights into potential therapeutic strategies for these metabolic disorders.