High non‐esterified fatty acid concentrations promote expression and secretion of fibroblast growth factor 21 in calf hepatocytes cultured in vitro

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The periparturient period is vitally important to the health status and the reproductive performance of dairy cows. During this period, dairy cows experience a stressful transition from the pregnant, non‐lactating state to the non‐pregnant, lactating state (DeGaris & Lean, 2008). Post‐partum milk production leads to a large increase in energy requirements that cannot be met solely through dietary intake. As a result, dairy cows enter a negative energy balance (NEB) that is further aggravated by nutrient prioritization towards the mammary gland (Contreras & Sordillo, 2011; Leroy, Vanholder, Van Knegsel, Garcia‐Ispierto, & Bols, 2008). Under NEB conditions, cows start to mobilize their body reserves from adipose tissue, resulting in elevated plasma concentrations of non‐esterified fatty acids (NEFA). The liver is the most important organ for removing NEFA from the bloodstream (Drackley, 1999). In the liver, NEFA can undergo mitochondrial β‐oxidation to produce energy. However, excessive NEFA will be incompletely oxidized by the liver to generate ketone bodies or re‐esterified to form triacylglycerols (TAG), thereby potentially resulting in the development of metabolic disorders associated with NEB, such as ketosis and fatty liver (Bobe, Young, & Beitz, 2004). These disorders are associated with increased veterinary costs, longer calving intervals, decreased milk production and decreased average lifetime of cows, thereby causing huge economic losses for the dairy industry.
Fibroblast growth factor 21 (FGF21) is predominantly expressed in liver and adipose tissue (Ding et al., 2012). In dairy cows, most circulating FGF21 originates from the liver (Schoenberg et al., 2011). FGF21 has been identified as a hormonal factor involved in the regulation of metabolic adaptations, such as promotion of hepatic lipid oxidation and ketogenesis, during energy deprivation (Schlegel et al., 2013). Nutritional status can drive expression and secretion of FGF21 in human, mouse and bovine subjects (Loor et al., 2007). Under fasting conditions, expression levels of FGF21 are strongly upregulated in liver and white adipose tissue (Badman et al., 2007). However, the direct effects of high concentrations of NEFA, as one of the important indicators of NEB, on FGF21 expression and secretion in hepatocytes from cows are not entirely clear. Therefore, the aim of this study was to determine the effects of NEFA on FGF21 expression and secretion in bovine hepatocytes cultured in vitro.
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