Dietary disodium fumarate relieves high-concentrate diet-induced hepatic injury by inhibiting endoplasmic reticulum stress, mitochondrial dysfunction and autophagy via epigenetic modifications in lactating hu sheep.

A high-concentrate diet fed to ruminants induced the release of LPS from the rumen to the liver. Dietary disodium fumarate (DF) fed to ruminants helps restore rumen homeostasis by improving the pH of the rumen fluid. However, the effects of dietary disodium fumarate on hepatic injury induced by high-concentrate diet have not been thoroughly explored. Eighteen lactating Hu sheep with rumen fistula were randomly divided into three groups: the low-concentrate diet group (LC, forage:concentrate=7:3, n=6), the high-concentrate diet group (HC, forage:concentrate=3:7, n=6) and the high-concentrate diet with DF supplementation group (FHC, 10g DF per sheep daily, n=6). After 8 weeks, the rumen fluid, portal vein and hepatic blood and liver tissue were collected for analysis. A high-concentrate diet decreased the pH of the rumen fluid and increased the LPS concentration in portal vein blood, resulting in morphological damage and an inflammatory response. GRP78-regulated unfolded protein response receptors and CHOP were upregulated, indicating ER stress; The imbalance between fusion and fission, mitophagy and PGAM5 upregulation indicated the mitochondrial damage in the liver of the HC group. Dietary DF supplementation relieved these hepatic injuries, accompanied by reduced autophagy. The level of methylation and chromatin compaction of ER stress- and autophagy-related genes were also increased by DF supplementation. These epigenetic modifications were negatively correlated with the mRNA expression of the target genes. Therefore, DF supplementation alleviated the inflammatory response, ER stress, and mitochondrial damage, not only by reducing LPS release but also through epigenetic modifications in the livers of Hu sheep fed a high-concentrate diet.