High blood concentrations of
nonesterified fatty acids (
NEFA) and altered lipid metabolism are key characteristics of
fatty liver in dairy cows. In nonruminants, the mitochondrial membrane
protein mitofusin 2 (MFN2) plays important roles in regulating mitochondrial function and intrahepatic lipid metabolism. Whether MFN2 is associated with hepatic lipid metabolism in dairy cows with moderate
fatty liver is unknown. Therefore, to investigate changes in MFN2 expression and
lipid metabolic status in dairy cows with moderate
fatty liver, blood and liver samples were collected from healthy dairy cows (n = 10) and cows with moderate
fatty liver (n = 10). To determine the effects of MFN2 on lipid metabolism in vitro, hepatocytes isolated from healthy calves were used for
small interfering RNA-mediated silencing of MFN2 or adenovirus-mediated overexpression of MFN2 for 48 h, or treated with 0, 0.6, 1.2, or 2.4 mM
NEFA for 12 h. Milk production and plasma
glucose concentrations in dairy cows with moderate
fatty liver were lower, but concentrations of
NEFA and β-hydroxybutyrate (BHB) were greater in dairy cows with moderate
fatty liver. Dairy cows with moderate
fatty liver displayed hepatic
lipid accumulation and lower abundance of hepatic MFN2,
peroxisome proliferator-activated receptor-α (PPARα), and
carnitine palmitoyltransferase 1A (CPT1A). However,
sterol regulatory element-binding protein 1c (SREBP-1c),
acetyl CoA carboxylase 1 (ACACA),
fatty acid synthase (FASN), and
diacylglycerol acyltransferase 1 (DGAT1) were more abundant in the livers of dairy cows with moderate
fatty liver. In vitro, exogenous
NEFA treatment upregulated abundance of
SREBP-1c, ACACA, FASN, and DGAT1, and downregulated the abundance of PPARα and CPT1A. These changes were associated with greater
lipid accumulation in calf hepatocytes, and MFN2 silencing aggravated this effect. In contrast, overexpression of MFN2-ameliorated exogenous
NEFA-induced
lipid accumulation by downregulating the abundance of
SREBP-1c, ACACA, FASN, and DGAT1, and upregulating the abundance of PPARα and CPT1A in calf hepatocytes. Overall, these data suggest that one cause for the negative effect of excessive
NEFA on hepatic
lipid accumulation is the inhibition of MFN2. As such, these mechanisms partly explain the development of hepatic steatosis in dairy cows.