Monensin supplementation downregulated the expression signature of genes involved in cholesterol synthesis in the ruminal epithelium and adipose tissue of lambs.

To understand the metabolic mechanisms regulating lipid metabolism by monensin, Afshari male lambs (n = 16) with 41.0 ± 2.4 kg body weight (BW, mean ± SD) at approximately 180 days of age were randomly assigned equally to two dietary treatments. After a 21-day pre-adaptation period, all animals in two groups continued to receive the basal diet, but one group received no monensin supplementation (control) while the other group received 30 mg/day of monensin per animal. Individual BW was recorded weekly to determine the average daily body weight gain (ADG). At the end of the 56-day experimental period, lambs were weighed and slaughtered. Monensin supplementation did not affect BW, ADG, and rumen fermentation characteristics. However, monensin significantly downregulated the sterol regulatory element-binding protein (SREBP)-2 gene expression in all sample tissues (p < 0.05). Also, monensin downregulated expressions of SREBP-1c and peroxisome proliferator-activated receptor (PPAR)-γ in back fat tissues. Monensin increased the expression of 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS)-2, but it decreased the mRNA abundance of HMGCS-1 in the rumen epithelial tissues (p < 0.05). Our data suggest that monensin downregulates cholesterol synthesis via inhibition of HMGCS-1 and impairment of the SREBP pathway, probably due to a crosstalk among different tissues to control energy metabolism.