PMID- 37268562
OWN - NLM
STAT- MEDLINE
DCOM- 20230724
LR  - 20230724
IS  - 1525-3198 (Electronic)
IS  - 0022-0302 (Linking)
VI  - 106
IP  - 8
DP  - 2023 Aug
TI  - AdipoRon alleviates fatty acid-induced lipid accumulation and mitochondrial 
      dysfunction in bovine hepatocytes by promoting autophagy.
PG  - 5763-5774
LID - S0022-0302(23)00295-3 [pii]
LID - 10.3168/jds.2022-22723 [doi]
AB  - During the transition period in dairy cows, high circulating concentrations of 
      nonesterified fatty acids (NEFA) increase hepatic lipid deposits and are 
      considered a major pathological factor for liver damage. We investigated whether 
      AdipoRon, a synthetic small-molecule agonist of adiponectin receptors 1 and 2 
      shown to prevent liver lipid accumulation in nonruminants, could alleviate 
      NEFA-induced lipid accumulation and mitochondrial dysfunction. Bovine hepatocytes 
      were isolated from 5 healthy Holstein female newborn calves (1 d of age, 30-40 
      kg, fasting), and independently isolated hepatocytes from at least 3 different 
      calves were used for each subsequent experiment. The composition and 
      concentration of NEFA used in this study were selected according to hematological 
      criteria of dairy cows with fatty liver or ketosis. First, hepatocytes were 
      cultured with various concentrations of NEFA (0, 0.6, 1.2, or 2.4 mM) for 12 h. 
      In a second experiment, hepatocytes were treated with AdipoRon at different 
      concentrations (0, 5, 25, or 50 muM for 12 h) and times (25 muM for 0, 6, 12, or 24 
      h) with or without NEFA (1.2 mM) treatment. In the last experiment, hepatocytes 
      were treated with AdipoRon (25 muM), NEFA (1.2 mM), or both for 12 h after 
      treatment with or without the autophagy inhibitor chloroquine. Hepatocytes 
      treated with NEFA had increased protein abundance of sterol regulatory 
      element-binding protein 1c (SREBP-1c) and mRNA abundance of acetyl-CoA 
      carboxylase 1 (ACACA), and decreased protein abundance of peroxisome 
      proliferator-activated receptor alpha (PPARA), proliferator-activated receptor gamma 
      coactivator-1 alpha (PGC-1alpha), mitofusin 2 (MFN2), cytochrome c oxidase subunit IV 
      (COX IV), and mRNA abundance of carnitine palmitoyltransferase 1A (CPT1A), along 
      with lower ATP concentrations. AdipoRon treatment reversed these effects, 
      suggesting this compound had a positive effect on lipid metabolism and 
      mitochondrial dysfunction during the NEFA challenge. In addition, upregulated 
      expression of microtubule-associated protein 1 light chain 3-II (LC3-II, encoded 
      by MAP1LC3) and downregulated expression of sequestosome-1 (SQSTM1, also called 
      p62) indicated that AdipoRon enhanced autophagic activity in hepatocytes. The 
      fact that chloroquine impeded the beneficial effects of AdipoRon on lipid 
      accumulation and mitochondrial dysfunction suggested a direct role for autophagy 
      during NEFA challenge. Our results suggest that autophagy is an important 
      cellular mechanism to prevent NEFA-induced lipid accumulation and mitochondrial 
      dysfunction in bovine hepatocytes, which is consistent with other studies. 
      Overall, AdipoRon may represent a promising therapeutic agent to maintain hepatic 
      lipid homeostasis and mitochondrial function in dairy cows during the transition 
      period.
CI  - (c) 2023, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the 
      American Dairy Science Association(R). This is an open access article under the CC 
      BY license (http://creativecommons.org/licenses/by/4.0/).
FAU - Zhao, Chenchen
AU  - Zhao C
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Wu, Bing
AU  - Wu B
AD  - Department of Neurosurgery, China-Japan Union Hospital of Jilin University, 
      Changchun, 130000, Jilin, China.
FAU - Li, Jinxia
AU  - Li J
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Jiang, Qianming
AU  - Jiang Q
AD  - Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of 
      Nutritional Sciences, University of Illinois, Urbana 61801.
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 - Liu, Menglin
AU  - Liu M
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Chen, Linfang
AU  - Chen L
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Zhu, Yiwei
AU  - Zhu Y
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Gao, Wenwen
AU  - Gao W
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Du, Xiliang
AU  - Du X
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Song, Yuxiang
AU  - Song Y
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Liu, Guowen
AU  - Liu G
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China.
FAU - Lei, Lin
AU  - Lei L
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China. Electronic address: jiluleilin@126.com.
FAU - Li, Xinwei
AU  - Li X
AD  - State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious 
      Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, 
      Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, 
      Changchun 130062, China. Electronic address: lixinwei100@126.com.
LA  - eng
PT  - Journal Article
DEP - 20230601
PL  - United States
TA  - J Dairy Sci
JT  - Journal of dairy science
JID - 2985126R
RN  - 0 (Fatty Acids)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (AdipoRon)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Cattle
MH  - Animals
MH  - Female
MH  - Fatty Acids/metabolism
MH  - Fatty Acids, Nonesterified/metabolism
MH  - Hepatocytes/metabolism
MH  - Liver/metabolism
MH  - *Fatty Liver/veterinary
MH  - Lipid Metabolism
MH  - Mitochondria/metabolism
MH  - Autophagy
MH  - RNA, Messenger/metabolism
MH  - *Cattle Diseases/metabolism
OTO - NOTNLM
OT  - AdipoRon
OT  - autophagy
OT  - lipid accumulation
OT  - mitochondrial dysfunction
OT  - nonesterified fatty acids
EDAT- 2023/06/03 11:42
MHDA- 2023/07/24 06:42
CRDT- 2023/06/02 22:01
PHST- 2022/09/01 00:00 [received]
PHST- 2023/01/28 00:00 [accepted]
PHST- 2023/07/24 06:42 [medline]
PHST- 2023/06/03 11:42 [pubmed]
PHST- 2023/06/02 22:01 [entrez]
AID - S0022-0302(23)00295-3 [pii]
AID - 10.3168/jds.2022-22723 [doi]
PST - ppublish
SO  - J Dairy Sci. 2023 Aug;106(8):5763-5774. doi: 10.3168/jds.2022-22723. Epub 2023 
      Jun 1.