Cdo1-Camkk2-AMPK axis confers the protective effects of exercise against NAFLD in mice
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ABSTRACT:
PROVIDER: PRJNA1000631 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25468509_1.fastq.gz | Fastqsanger.gz | |||
| SRR25468509_2.fastq.gz | Fastqsanger.gz | |||
| SRR25468510_1.fastq.gz | Fastqsanger.gz | |||
| SRR25468510_2.fastq.gz | Fastqsanger.gz | |||
| SRR25468511_1.fastq.gz | Fastqsanger.gz |
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Project description:Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) and exercise synergistically ameliorates NAFLD in male mice. Mechanistically, Cdo1 facilitates the binding between AMPK and kinase active Camkk2, which activates AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD
2023-08-07 | GSE239729 | GEO
Project description:Exercise is an effective non-pharmacological strategy for ameliorating nonalcoholic fatty liver disease (NAFLD), but the underlying mechanism needs further investigation. Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) decreases basal metabolic rate of the mice and impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) increases basal metabolic rate of the mice and synergizes with exercise to ameliorate NAFLD. Mechanistically, Cdo1 tethers Camkk2 to AMPK by interacting with both of them, thereby activating AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD.
| S-EPMC10728194 | biostudies-literature
Project description:Castration-resistant prostate cancer (CRPC) remains an incurable disease driven predominantly by aberrant androgen receptor AR signaling, suggesting that processes downstream of AR represent viable alternative targets for the treatment of CRPC. CAMKK2 (encoding calcium/calmodulin-dependent protein kinase kinase 2) is a direct AR target that is highly expressed during prostate cancer progression, a functional driver of the disease and hence, emerging therapeutic target. To date, CAMKK2’s oncogenic effects in prostate cancer have been attributed to its activation of AMP-activated protein kinase (AMPK), but recent reports suggest that CAMKK2 may also facilitate tumorigenesis through AMPK-independent mechanisms. Here, we demonstrate that AR-mediated CAMKK2 signaling promotes prostate cancer growth through an alternative downstream pathway involving calcium/calmodulin-dependent protein kinase I (CAMKI) and cAMP response element-binding protein (CREB). Unbiased transcriptomics identified CREB-mediated transcription as a CAMKK2-regulated process, findings that were validated using diverse molecular, genetic and pharmacological approaches in vitro and in vivo. CAMKK2 promoted CREB serine-133 phosphorylation and activation through CAMKIa independently of AMPK, CAMKIV or other CAMKI isoforms. Functionally, CREB activity was required for maximal CRPC growth. The CREB family members CREB1 and ATF1 exhibited close redundancy, necessitating co-targeting for optimal anti-tumor efficacy. Pharmacologically, a small molecule inhibitor of CREB1/ATF1, 666-15, blocked CRPC growth with minimal side effects in vitro and in vivo including in patient-derived xenograft models of enzalutamide resistance. Mechanistically, CAMKK2-mediated CREB increased prostate cancer growth through augmenting cholesterol metabolism. Together, these findings identified a novel oncogenic pathway in prostate cancer that could be exploited for the treatment of CRPC.
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Project description:Liver fibrosis occurs during chronic liver disease. Advanced liver fibrosis results in cirrhosis, liver failure and often requires liver transplantation. However, due to the lack of human models, mechanisms underlining the pathogenesis of liver fibrosis remain unclear. Recent studies implicated a central role of deranged lipid metabolism in its pathogenesis. In this study, we generated LEPTIN-deficient (LEPTIN-/-) pigs using zinc finger nuclease technology to investigate the mechanisms of liver fibrosis associated with obesity. The LEPTIN-/- pigs showed increased body fat and significant insulin resistance by 12 months of age. To resemble non-alcoholic fatty liver disease (NAFLD) patients, LEPTIN-/- pig developed the phenotypic features of fatty liver, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis with age. Meanwhile, LEPTIN absence reduced phosphorylation of JAK2-STAT3 and AMPK. The alteration of JAK2-STAT3 enhanced fatty acid β-oxidation, whereas inactivation of AMPK led to mitochondrial autophagy, and both contributed to increased oxidative stress in hepatocytes. Although Leptin deletion in the rat liver altered JAK2-STAT3 phosphorylation, it activated the AMPK pathway and prevented liver fibrogenesis in contrast with the LEPTIN-/- pig. To our knowledge, the LEPTIN-/- pig provides the first model recapitulating the full pathogenesis of NAFLD and its progression toward liver fibrosis. The activity of AMPK signaling pathway suggests a potential target for development of new strategies for the diagnosis and treatment of NAFLD.
2023-09-20 | GSE176023 | GEO
Project description:Macrophages play crucial roles in immunity and tissue homeostasis, exhibiting diverse phenotypes influenced by their microenvironment. While matrix stiffness is recognized as a key regulator of macrophage fate, the underlying mechanism remains elusive. Here, we investigate primary bone marrow-derived macrophages (BMDMs) in a physiologically relevant 3D environment using a dynamic stiffening collagen-based hydrogel system. We show that increasing matrix stiffness promotes BMDM polarization towards a pro-regenerative phenotype, characterized by elevated CD206 levels, and M2-like gene signature. Mechanistically, we identify the calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) as an important component of molecular machinery controlling BMDM response to stiff microenvironment. Surprisingly, the blocking of CaMKK2 does not interfere with the IL-4-induced pro-regenerative programs. On the contrary, the inhibition of this kinase abolishes phenotypic and transcriptional changes induced by stiffness, highlighting the specific function of the CaMKK2-STAT6 axis in macrophage mechanosensory signaling. Functionally, matrix stiffening promotes M2-like/pro-tumoral polarization of BMDM in a CaMKK2-dependent manner, confirming the critical role of this kinase in the tumor microenvironment and identifying a direct pro-tumoral effect mediated by Camkk2-signaling in macrophages. In a murine wound healing model, stiffened matrices drive immune cell recruitment and macrophage polarization towards a pro-regenerative phenotype, facilitating vascularization, while deletion of Camkk2 impairs this phenomenon. Our findings elucidate the mechanistic basis of matrix stiffness-mediated macrophage fate determination, identifying CaMKK2 as a druggable target to selectively modulate the mechanoresponsiveness of macrophages in malignant and injured tissues.
2025-04-30 | GSE273834 | GEO
Project description:To investigate the neuroprotective mechanism of mild hypothermia (MH) in ameliorating cerebral ischemia reperfusion (IR) injury. The Pulsinelli's four-vessel ligation method was utilized to establish a rat model of global cerebral IR injury. To investigate the role of S100A8 in MH treatment of cerebral IR injury, hippocampus-specific S100A8 loss or gain of function was achieved using an adeno-associated virus system. We examined the effect of S100A8 over-expression or knock-down on the function of the SH-SY5Y cell line subjected to oxygen-glucose deprivation reoxygenation (OGDR) injury under MH treatment and delved into the underlying mechanisms. MH significantly ameliorates IR-induced neurological injury in the brain. Similarly to MH, knock-down of S100A8 significantly reduced neuronal oxidative stress, attenuated mitochondrial damage, inhibited apoptosis, and improved cognitive function in IR rats. Conversely, over-expression of S100A8 attenuated MH's protective effect and aggravated brain IR injury. In vitro, low expression of S100A8 significantly inhibited the decline in mitochondrial membrane potential induced by OGDR, reduced oxidative stress response, and decreased cell apoptosis, acting as a protective agent nearly equivalent to MH in SH-SY5Y cells. However, over-expression of S100A8 significantly inhibited these protective effects of MH. Mechanistically, MH down-regulated S100A8 expression, enhancing mitochondrial function via activation of the CAMKK2/AMPK signaling pathway. Moreover, with MH treatment, the administration of CAMKK2 and AMPK inhibitors STO-609 and Dorsomorphin significantly increased oxidative stress, mitochondrial damage, and cell apoptosis, thereby diminishing MH's neuroprotective effect against cerebral IR injury. Our study identified S100A8 as a master regulator that enables MH to ameliorate neurological injury during the early stage of cerebral IR injury by enhancing mitochondrial function. By targeting the S100A8-initiated CAMKK2/AMPK signaling pathway, we may unlock a novel therapeutic intervention or develop a refined MH therapeutic strategy against cerebral IR injury.
| S-EPMC11754893 | biostudies-literature
Project description:To determine the function of Camkk2 in HSC we performed a microarray analysis on isolated KSL from WT and Camkk2 null mice. Using a threshold of 0.05 for statistical significance (p-value) and a log fold change of expression with absolute value of at least 0.6, 1831 differentially expressed genes (DEGs) were identified out of a total of 29352 genes with measured expression. When compared to WT KSL, 1289 genes were significantly downregulated and 533 genes were upregulated in Camkk2 null HSC. The genes downregulated in Camkk2 null KSL were strongly enriched in HSC, early progenitors and lymphoid-myeloid-affiliated genes (s-myly) primed in HSC. Of note, HSC-affiliated genes found downregulated in Camkk2 KSL included Hlf, Meis1, Pbx-1 and Prdm5 which are 4 of the 8 genes capable to reprogram committed murine blood cells into HSC. The GSEA analysis also showed that genes affiliated with the late progenitor signature and erythroid genes primed in HSC and GMP specific genes (d-my) were significantly upregulated in Camkk2 null KSL. These findings indicate Camkk2 controls crucial transcriptional programs involved in the mechanism of HSC differentiation and lineage commitment.
2018-02-13 | GSE95733 | GEO
Project description:Genetic AMPK activation in liver protects against diet-induced obesity and NAFLD
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Project description:We developed a GEMM in which AMPK can be inducibly activated in vivo (iAMPK mice). We provide here the data (RNA seq) on the transcriptional changes induced by AMPK activation in livers from mice fed a high-fat diet.
2019-02-05 | GSE122767 | GEO
Project description:The 5' AMP-activated protein kinase (AMPK) is a master energy sensing kinase that is regulated by phosphorylation of Thr172 in its activation loop. Three kinases can phosphorylate AMPK at Thr172: the tumor suppressor LKB1, CAMKK2 and TAK1. While LKB1- and CAMKK2-mediated AMPK Thr172 phosphorylation have been well-characterized, much less is known about TAK1-dependent AMPK phosphorylation. An important target of TAK1 is IκB kinase (IKK) which controls NF-B transcription factor activation. Here, we tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for phosphorylation of Thr172 in AMPK in response to treatment with IL-1 or TNF- treatment or by TAK1 overexpression. Additionally, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could lead to AMPK activation. We found that IKK directly phosphorylated AMPK at Thr172 independently of LKB1 or energy stress. This finding indicated that while LKB1 activates AMPK as a sensor of energetic stress, IKK activated AMPK in response to extracellular inflammatory signals and through distinct pathways downstream of IKK activation. Accordingly, in LKB1-deficient cells, IKK inhibition caused a reduction in AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers.
2018-07-16 | PXD009897 | Pride