Short communication: Enhanced autophagy activity in liver tissue of dairy cows with mild fatty liver

Chen, Meng; Loor, Juan J.; Zhai, Qian; Liang, Yusheng; Yu, Hao; Du, Xiliang; Shen, Taiyu; Fang, Zhiyuan; Wang, Xinghui; Zhu, Yiwei; Song, Yuxiang; Liu, Zhaoxi; Li, Xiaobing; Wang, Zhe; Li, Xinwei

doi:10.3168/jds.2019-17457

Cited by 13 publications

(16 citation statements)

References 41 publications

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“…Our results indicate that NEFA can promote the protein expression of ATG7, p62, BECN1, and LC3-II in hepatocytes and increase the number of autophagosomes ( Figure 3 and Figure 4 ), which clearly demonstrates that NEFA promotes autophagosome formation in hepatocytes. In line with our results, Chen et al indicated that enhanced formation and degradation of autophagosomes were found in the liver of cows with mild fatty liver during the perinatal period [ 15 ]. Moreover, Li et al previously suggested that activation of autophagy and an increase in the number of autophagosomes were found in the mammary tissues of cows with hyperketonemia [ 30 ].…”

Section: Discussionsupporting

confidence: 92%

“…Autophagy is a catabolic process in which the damaged cytoplasmic organelles or cytosolic components are degraded by lysosomal proteases, and it can contribute to modulating lipid metabolism by directly regulating lipid degradation [ 13 , 14 ]. A number of previous studies have shown that dairy cows with mild fatty liver show a more active lipid metabolism and enhanced autophagy, which serve as adaptive mechanisms of dairy cows during the perinatal period [ 15 , 16 ]. Therefore, when the liver is exposed to a high blood concentration of NEFA, autophagy plays an important role in maintaining the stability of hepatocytes, thereby providing nutrients and alleviating lipid accumulation.…”

Section: Introductionmentioning

confidence: 99%

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NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

Huang

Zhao

Liu

et al. 2021

Animals

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During the perinatal period, the abnormally high plasma non-esterified fatty acids (NEFA) concentration caused by the negative energy balance (NEB) can impose a significant metabolic stress on the liver of dairy cows. Endoplasmic reticulum (ER) stress is an important adaptive response that can serve to maintain cell homeostasis in the event of stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is the most rapidly activated cascade when ER stress occurs in cells and has an important impact on the regulation of hepatic lipid metabolism and autophagy modulation. However, it is unknown whether NEFA can affect autophagy through modulating the PERK pathway, under NEB conditions. In this study, we provide evidence that NEFA treatment markedly increased lipid accumulation, the phosphorylation level of PERK and eukaryotic initiation factor 2α (eIF2α), and the expression of glucose-regulated protein 78 (Grp78), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). More importantly, NEFA treatment can cause a substantial increase in the protein levels of autophagy-related gene 7 (ATG7), Beclin-1 (BECN1), sequestosome-1 (p62), and microtubule-associated protein 1 light chain 3 (LC3)-II, and in the number of autophagosomes in primary bovine hepatocytes. The addition of GSK2656157 (PERK phosphorylation inhibitor) can significantly inhibit the effect of NEFA on autophagy and can further increase lipid accumulation. Overall, our results indicate that NEFA could promote autophagy via the PERK pathway in bovine hepatocytes. These findings provide novel evidence about the potential role of the PERK signaling pathway in maintaining bovine hepatocyte homeostasis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

Huang

Zhao

Liu

et al. 2021

Animals

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“…In dairy cows, autophagy is altered during metabolic disorders in the transition period. Enhanced autophagic activity in the liver and mammary gland has been associated with response mechanisms to alleviate metabolic stress induced by mild fatty liver and hyperketonemia (Chen et al, 2020;Li et al, 2020). At least in nonruminants experiencing metabolic disorders associated with adipose tissue dysfunction, autophagy is stimulated by oxidative stress (Zhang et al, 2012;Mizunoe et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Adenosine 5′-monophosphate-activated protein kinase ameliorates bovine adipocyte oxidative stress by inducing antioxidant responses and autophagy

Fan

Loor

et al. 2021

Journal of Dairy Science

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“…Increasing activity of mTORC1 inhibited ATGL abundance in epididymal fat of mice (Chakrabarti et al, 2013). Although our previous work has indicated that autophagy was an important biological mechanism in cows with fatty liver (Du et al, 2018;Chen et al, 2020), the potential role of autophagy in the lipolytic response during the peripartal period is unknown.…”

Section: Introductionmentioning

confidence: 98%

Increased adipose tissue lipolysis in dairy cows with fatty liver is associated with enhanced autophagy activity

Dong

Yue

Loor

et al. 2022

Journal of Dairy Science

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Lipolysis is increased in adipose tissue of cows with fatty liver during the transition period. Autophagy, a major cellular degradation process, plays a critical role in adipose tissue homeostasis. The objective of this study was to explore the relationship between lipolysis and autophagy in adipose tissue of cows with fatty liver. Using a nested case-control design, we compared blood and adipose tissue samples from 10 control cows [parity: median = 3, range = 2-4; days in milk: median = 8 d, range = 5-10 d; hepatic triacylglycerol content: median = 0.55% liver wt, range = 0.48-0.61% liver wt] and 10 lactation stage-matched cows with fatty liver (parity: median = 3, range = 2-4; days in milk: median = 9 d, range = 5-11 d; hepatic triacylglycerol content: median = 6.28% liver wt, range = 2.86-7.75% liver wt). Data were analyzed using paired t-tests. Serum concentrations of free fatty acids and β-hydroxybutyrate were greater and glucose concentration was lower in cows with fatty liver, which we determined by using commercially-available kits. Furthermore, western blotting showed that increased protein abundance of ATGL (adipose triglyceride lipase), ATG5 (autophagyrelated gene 5), and ATG7; ratio of phosphorylated (p)-HSL (hormone-sensitive lipase) to HSL and MA-P1LC3 (microtubule-associated protein 1 light chain 3, also called LC3-II) to LC3-I along with decreased abundance of PLIN1 (perilipin 1), SQSTM1 (sequestosome-1, also called p62), and the ratio of p-mTOR (phosphorylated mechanistic target of rapamycin) to mTOR in cows with fatty liver. Quantitative reversetranscription PCR revealed an increase in abundance of MAP1LC3 mRNA and a decrease in SQSTM1 mRNA in cows with fatty liver. These findings were replicated using an adipocyte model. Primary cultures of calf adipocytes isolated from the adipose tissue of the peritoneal omentum and mesentery were treated with 10 mM 3-methyladenine (3-MA), 5 nM rapamycin, 1 µM isoproterenol (ISO), and 1 µM ISO + 10 mM 3-MA. Comparisons among groups were analyzed using one-way ANOVA. Compared with the control, the 1 µM ISO treatment upregulated the abundance of ATGL, the ratio of p-HSL to HSL and LC3-II to LC3-I, and the glycerol content, whereas it downregulated the abundance of PLIN1 and p62 in calf adipocytes. Compared with the 1 µM ISO treatment group, 1 µM ISO + 10 mM 3-MA downregulated the abundance of ATGL, the ratio of p-HSL to HSL and LC3-II to LC3-I, and the glycerol content, whereas it upregulated the abundance of PLIN1 and p62. Compared with the control, the 5 nM rapamycin treatment upregulated the abundance of ATGL, the ratio of p-HSL to HSL and LC3-II to LC3-I, and the glycerol content, whereas it downregulated the abundance of PLIN1 and p62 in calf adipocytes. Overall, these data indicated that increased lipolysis in adipose tissue of cows with fatty liver was associated with enhanced autophagy. However, the specific molecular mechanisms that link lipolysis and autophagy need to be further investigated.

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Short communication: Enhanced autophagy activity in liver tissue of dairy cows with mild fatty liver

Cited by 13 publications

References 41 publications

NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

Adenosine 5′-monophosphate-activated protein kinase ameliorates bovine adipocyte oxidative stress by inducing antioxidant responses and autophagy

Increased adipose tissue lipolysis in dairy cows with fatty liver is associated with enhanced autophagy activity

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