Dataset Information

FGF21-MAPK1 Imbalance Disrupts Hepatic Lipid Metabolism in Dairy Cow Ketosis.

ABSTRACT:

Background

Aberrant hepatic lipid metabolism is a key predisposing factor for dairy cow ketosis, with genetic factors playing a pivotal role in disease pathogenesis. However, systematic screening and functional validation of candidate genes for bovine ketosis remain limited. In this study, we aimed to identify genetic markers associated with clinical ketosis and explore their potential functional mechanisms underlying disease susceptibility.

Methods

We conducted simplified genome sequencing (SuperGBS), genome-wide association studies (GWAS), and Sanger sequencing on Chinese Holstein cows, both healthy and with ketosis.

Results

We reported that mitogen-activated protein kinase 1 (MAPK1) was significantly associated with clinical ketosis. Further investigation revealed concurrent upregulation of MAPK1 protein and disrupted hepatic lipid homeostasis in hepatocytes from in vivo and in vitro models. Critically, siRNA-mediated knockdown of MAPK1 reversed lipid metabolism processes and reduced lipid accumulation in β-Hydroxybutyric acid (BHB)-exposed bovine hepatocytes, thereby establishing MAPK1 activation as a driver of lipotoxicity in dairy cow ketosis. Additionally, we identified that supplementation of fibroblast growth factor 21 (FGF21) fusion protein not only reduced MAPK1 expression but also normalized hepatic lipid metabolism in BHB-exposed bovine hepatocytes.

Conclusions

FGF21-MAPK1 imbalance is a reason for hepatic lipid metabolic dysfunction, providing a potential intervention approach to mitigate dairy cows' ketosis.

SUBMITTER: Xu JJ

PROVIDER: S-EPMC12470934 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature

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Publications

FGF21-MAPK1 Imbalance Disrupts Hepatic Lipid Metabolism in Dairy Cow Ketosis.

Xu Jun-Jie JJ Yang Fan F Chen Zhi-Xi ZX Wang Zhi-Peng ZP Wang Zi-Xuan ZX Deng Zi-Han ZH Xu Chen-Jie CJ Chen Fang-Hui FH Zhang Wei W Liu Yang Y Cai Ya-Fei YF

Life (Basel, Switzerland) 20250824 9

<h4>Background</h4>Aberrant hepatic lipid metabolism is a key predisposing factor for dairy cow ketosis, with genetic factors playing a pivotal role in disease pathogenesis. However, systematic screening and functional validation of candidate genes for bovine ketosis remain limited. In this study, we aimed to identify genetic markers associated with clinical ketosis and explore their potential functional mechanisms underlying disease susceptibility.<h4>Methods</h4>We conducted simplified genome ...[more]

PMID: 41010281

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Project description:Chronic stress leads post-traumatic stress disorder (PTSD) and to metabolic complications, including fatty liver. It is feasible, that stress immediately initiates molecular mechanisms to alter energy metabolism and glucose homeostasis which interfere with hepatic lipid accumulation after stress recovery. We aim to elucidate these molecular mechanisms of long term stress effects on metabolism and focus on physiological adaptation and the role of FGF21, which is protective in hepatic lipid accumulation. Methods FGF21 knockout and control mice were exposed to chronic variable stress (Cvs) and recovered for 3 months to simulate PTSD. We determined in vivo and ex vivo energy metabolism, mitochondrial function by extracellular flux analysis, alterations in DNA modifying enzymes and gene regulation immediately after stress and after the recovery period to determine long term alterations. Results Chronic stress leads to reduced insulin sensitivity and hepatic lipid accumulation with increased fatty acid uptake (FAU), stress-induced lipolysis, and reduction in NAD+/NAD ratio and Sirt activity. Immediately after stress, PPARa and SREBP-1 target genes are differentially regulated and are involved in the development of stress-induced fatty liver. After recovery, insulin sensitivity increases but insulin-induced de novo lipogenesis (DNL) is reduced and FAU is increased. HDAC and MT activity are suppressed, whereas HAT activity increases, linking metabolic adjustments to transcriptional regulators. Thus, key metabolic genes are differentially regulated and secreted proteins indicate the activation of liver disease by Cvs only in FGF21WT. GR binding to the Cd36 promoter is altered. After stress recovery, serum FGF21 is increased and protects against lipid accumulation. FGF21 interacts by attenuating DNL, increasing FAU and HAT activity, and balancing mitochondrial activity. Higher long-term stress-induced activation and binding of GR to the FGF21 promoter may contribute to the prolonged FGF21 release. Conclusions We show that previous stress exposure determines predisposition to fatty liver disease is regulated by FGF21. Immediately after Cvs, altered gene regulation and activity of DNA-modifying enzymes determine the metabolic late effects seen in PTSD. FGF21 functions after chronic stress exposure i) to protect against hepatic lipid accumulation, ii) to maintain mitochondrial capacity, and iii) to mediate in the modulation of DNA-modifying enzymes. These findings highlight the protective role of FGF21 even in stress-induced hepatic lipid accumulation.

Dataset Information

FGF21-MAPK1 Imbalance Disrupts Hepatic Lipid Metabolism in Dairy Cow Ketosis.

Background

Methods

Results

Conclusions

Publications

FGF21-MAPK1 Imbalance Disrupts Hepatic Lipid Metabolism in Dairy Cow Ketosis.

Similar Datasets

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