Research progress on the regulatory mechanisms of gluconeogenesis in the liver of dairy cows

Glucose serves as the core energy substrate driving milk synthesis and the fundamental structural unit for lactose synthesis, with its supply level directly determining the efficiency of milk production in dairy cows. However, the unique rumen microbial fermentation characteristics of dairy cows result in a significant portion of dietary glucose being converted into volatile fatty acids. Consequently, more than 80% of glucose in the body relies on hepatic gluconeogenesis. Therefore, it is crucial to deeply understand the regulatory mechanisms of hepatic gluconeogenesis in dairy cows to ensure their healthy and efficient production. This review systematically examines hepatic gluconeogenesis in dairy cows. First, it clarifies that the portal vein zone and central vein zone constitute the primary cellular compartments executing gluconeogenic functions based on liver structure and functional zonation. Second, it explores substrate preferences in hepatic gluconeogenesis, demonstrating that propionic acid serves as the predominant carbon source for gluconeogenesis in adult dairy cow livers, contributing 60%–74% of total carbon input. Furthermore, it provides a detailed overview of gluconeogenesis regulatory elements, mapping a coordinated regulatory network involving multiple transcription factors such as cAMP-response element binding protein (CREB), forkhead transcription factor O1 (FOXO1), peroxisome proliferator-activated receptor γ coactivator 1-alpha (PGC-1α), and hepatic nuclear factor 4 alpha (HNF4α). Finally, the present review outlines future research directions based on the current studies, aiming to provide theoretical foundations and technical support for improving glucose metabolism and enhancing production efficiency in dairy cows.