ANGPTL8, also known as betatrophin, is an important cytokine and a novel but atypical member of the ANGPTL family. It plays a crucial role in modulating serum glucose and lipid metabolism, especially in regulating lipoprotein lipase (LPL) activity, which is key for fatty acid uptake into tissues [2,3,4,5,6,7,8,9,10]. It has been associated with pathways like NFκB-mediated inflammation and ERK signaling. It is significantly increased in metabolic disorder-related diseases such as type 2 diabetes mellitus (T2DM), obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD), making it an important target for research into these conditions [3,10]. Gene knockout (KO) mouse models have been valuable in understanding its functions [1].

ANGPTL8 KO mouse studies demonstrated that ANGPTL8 deficiency suppresses high-fat diet (HFD)-stimulated inflammatory activity, hepatic steatosis, and liver fibrosis. The restoration of liver ANGPTL8 expression in KO mice accelerated HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a pro-inflammatory factor, activates hepatic stellate cells (HSCs) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes promoting liver fibrosis [1].

In conclusion, ANGPTL8 is a key regulator in metabolic homeostasis, with a significant impact on lipid and glucose metabolism. The use of ANGPTL8 KO mouse models has revealed its role in accelerating NAFLD-associated liver fibrosis, highlighting its potential as a diagnostic marker and therapeutic target for liver-related metabolic diseases [1].