Lithium Chloride Promotes Milk Protein and Fat Synthesis in Bovine Mammary Epithelial Cells via HIF-1α and β-Catenin Signaling Pathways.

Abstract

Lithium is one of the trace elements with many physiological properties, such as being anti-cancer, anti-viral, and anti-inflammatory. However, little is known about its effect on milk synthesis during lactation. Therefore, we selected different concentrations (5mM, 10mM, and 20mM) of lithium chloride (LiCl) and assessed the effect of LiCl on bovine mammary epithelial (MAC-T) cells that underwent 4days of differentiation induction. Moreover, we analyzed the effect of LiCl on the expression of genes related to milk fat and milk protein synthesis. Herein, LiCl (5-20mM) significantly increased the expression of β-casein, promoted mRNA expression and phosphorylated protein expression of the signal transduction molecule and activator of transcription 5β (STAT5-β), and inhibited mRNA and protein expression of suppressor of cytokine signaling 2 (SOCS2). In contrast, 5 and 10mM LiCl significantly inhibited expression of SOCS3. LiCl at concentration of 5-20mM enhanced phosphorylation level of mTOR protein; at 10mM and 20mM, LiCl significantly promoted expression and phosphorylation of downstream ribosomal protein S6 kinase beta-1 (S6K1) protein. Considering milk fat synthesis, mRNA expression of acetyl CoA carboxylase (ACC) and lipoprotein lipase (LPL) genes was considerably increased in the presence of LiCl (5-20mM). Additionally, increased protein expression levels of stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor-γ (PPARγ), and sterol regulatory element-binding protein 1 (SREBP1) were observed at all LiCl concentrations tested. Subsequently, LiCl (5-20mM) significantly promoted protein expression and phosphorylation of β-catenin, while 10mM and 20mM of LiCl significantly promoted protein expression of hypoxia-inducible factor-1α (HIF-1α). Collectively, it has been shown that 10mM LiCl can effectively activate HIF-1α, β-catenin, and β-catenin downstream signaling pathways. Conversely, at 10mM, LiCl inhibited SOCS2 and SOCS3 protein expression through JAK2/STAT5, mTOR, and SREBP1 signaling pathways, improving synthesis of milk protein and fat. Therefore, LiCl can be used as a potential nutrient to regulate milk synthesis in dairy cows.