Pck1, also known as phosphoenolpyruvate carboxykinase 1 (PEPCK1), is a key rate-limiting enzyme in gluconeogenesis, catalyzing the conversion of oxaloacetate to phosphoenolpyruvate [4]. It is involved in multiple biological processes and metabolic pathways, such as maintaining fasting glucose levels, affecting renal physiology, and being related to ammoniagenesis and cataplerosis in the liver [3,5]. Genetic models, especially KO and CKO mouse models, have been crucial in studying its functions.

In male mice, liver Pck1 deficiency promotes metabolic-associated fatty liver disease (MAFLD) through the activation of the PI3K/AKT/PDGF axis. Pck1-deficient male mice show hepatic lipid disorder, liver injury, and aggravated fibrosis and inflammation when on a high-fat diet. Forced expression of hepatic PCK1 ameliorates MAFLD [1]. In the context of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), combined knockdown of Ppara and Pck1 in vivo abolishes the beneficial outcomes of a 5:2 intermittent fasting regimen against inflammation and fibrosis, while overexpression of Pck1 alone or with Ppara lowers hepatic triglycerides and steatosis [2]. In diabetic nephropathy mouse models, Pck1 overexpression in proximal tubules protects against albuminuria, PT cell apoptosis, and mitoribosomal defects, while Pck1 deficiency leads to these adverse phenotypes [3].

In conclusion, Pck1 is essential for various biological functions including maintaining metabolic homeostasis, protecting against mitoribosomal defects, and regulating acid-base balance. Studies using Pck1 KO/CKO mouse models have revealed its crucial roles in diseases like MAFLD, NASH, HCC, and diabetic nephropathy, providing insights into potential therapeutic strategies for these conditions.