PMID- 31178189 OWN - NLM STAT- MEDLINE DCOM- 20191021 LR - 20191022 IS - 1525-3198 (Electronic) IS - 0022-0302 (Linking) VI - 102 IP - 8 DP - 2019 Aug TI - Low abundance of mitofusin 2 in dairy cows with moderate fatty liver is associated with alterations in hepatic lipid metabolism. PG - 7536-7547 LID - S0022-0302(19)30505-3 [pii] LID - 10.3168/jds.2019-16544 [doi] AB - 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 beta-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-alpha (PPARalpha), 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 PPARalpha 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 PPARalpha 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. CI - Copyright (c) 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved. FAU - Dong, Jihong AU - Dong J AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Loor, Juan J AU - Loor JJ AD - Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801. FAU - Zuo, Rankun AU - Zuo R AD - College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China. FAU - Chen, Xiying AU - Chen X AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Liang, Yusheng AU - Liang Y AD - Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801. FAU - Wang, Yazhe AU - Wang Y AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Shu, Xin AU - Shu X AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Sun, Xudong AU - Sun X AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Jia, Hongdou AU - Jia H AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Liu, Guowen AU - Liu G AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Wang, Zhe AU - Wang Z AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Li, Xiaobing AU - Li X AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. FAU - Li, Xinwei AU - Li X AD - Key Laboratory of Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China. Electronic address: lixinwei100@126.com. LA - eng PT - Journal Article DEP - 20190606 PL - United States TA - J Dairy Sci JT - Journal of dairy science JID - 2985126R RN - 0 (Fatty Acids, Nonesterified) RN - 0 (PPAR alpha) RN - 0 (Sterol Regulatory Element Binding Protein 1) RN - EC 2.3.1.20 (Diacylglycerol O-Acyltransferase) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - TZP1275679 (3-Hydroxybutyric Acid) SB - IM MH - 3-Hydroxybutyric Acid/metabolism MH - Animals MH - Cattle/genetics/*metabolism MH - Cattle Diseases/enzymology/genetics/*metabolism MH - Diacylglycerol O-Acyltransferase/genetics/metabolism MH - Fatty Acids, Nonesterified/metabolism MH - Fatty Liver/enzymology/genetics/metabolism/*veterinary MH - Female MH - GTP Phosphohydrolases/genetics/*metabolism MH - Hepatocytes/enzymology/metabolism MH - *Lipid Metabolism MH - Liver/*metabolism MH - Mitochondria/metabolism MH - PPAR alpha/genetics/metabolism MH - Sterol Regulatory Element Binding Protein 1/genetics/metabolism OTO - NOTNLM OT - dairy cows OT - lipid metabolism OT - mitofusin 2 OT - moderate fatty liver EDAT- 2019/06/11 06:00 MHDA- 2019/10/23 06:00 CRDT- 2019/06/11 06:00 PHST- 2019/02/25 00:00 [received] PHST- 2019/04/18 00:00 [accepted] PHST- 2019/06/11 06:00 [pubmed] PHST- 2019/10/23 06:00 [medline] PHST- 2019/06/11 06:00 [entrez] AID - S0022-0302(19)30505-3 [pii] AID - 10.3168/jds.2019-16544 [doi] PST - ppublish SO - J Dairy Sci. 2019 Aug;102(8):7536-7547. doi: 10.3168/jds.2019-16544. Epub 2019 Jun 6.