The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30

Li, Longlong; Wang, Hongjun; Yao, Yao; Cao, Ji; Jiang, Zhihao; Yan, Weiyuan; Xu, Chuang; Li, Qian; Lu, Miaomiao; Ma, Haitian

doi:10.1016/j.redox.2021.102187

Cited by 20 publications

(33 citation statements)

References 48 publications

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“…Interestingly, both FLHS in laying hens and NAFLD in humans are have the similarity pathology features and clinical symptoms that characterized as the lipid metabolism disorders, inflammatory response and oxidative stress in the liver, and also simultaneously accompanied by obesity and dyslipidemia. Many researchers, including our laboratory, have found that the activation of AMPK signal can protect against the occurrence and development of NAFLD that presented as mitigative effect on the hepatic steatosis, inflammatory response and oxidative stress in mammals ( Hu et al, 2021 ; Li et al, 2021 ; Wan et al, 2021 ). However, whether AMPK acts a crucial role in the occurrence and development of FLHS remains elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The methods of protein extraction and western blot analysis of chicken hepatocytes was referred to our recent description ( Li et al, 2021 ). Briefly, the primary chicken hepatocytes were homogenized in the RIPA lysis buffer (Beyotime Institute of Biotechnology, Shanghai, China) with 1% protease and phosphatase inhibitors (Beyotime Institute of Biotechnology, Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

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Activated AMP-activated protein kinase prevents hepatic steatosis, oxidative stress and inflammation in primary chicken hepatocytes

Yao

Yang

et al. 2022

Front. Physiol.

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Fatty liver hemorrhagic syndrome (FLHS) in laying hens, a nutritional metabolic disorder disease, can lead to the decline of laying rate, shortening of laying peak period and increase of mortality, which seriously constrain the sustainable development of layer industry. Until now, there is no effective strategies can prevent and control the occurrence of fatty liver hemorrhagic syndrome in laying hens. The AMP-activated protein kinase (AMPK), a major sensor of cellular energy status, acts a crucial role in regulating lipid metabolism, oxidative stress and inflammatory responses in body. However, the potential molecular mechanisms about AMP-activated protein kinase signal in controlling the occurrence of fatty liver hemorrhagic syndrome are remain unclear. In present study, we found that the phosphorylated AMP-activated protein kinase (Thr172) protein level was markedly reduced in palmitic acid plus oleic acid (PO)-induced primary chicken hepatocytes. Moreover, blocked AMP-activated protein kinase signal by AMP-activated protein kinase inhibitor compound C obviously exacerbated lipid metabolism disorders, oxidative stress and inflammatory response triggered by palmitic acid plus oleic acid in primary chicken hepatocytes. Nevertheless, the lipid metabolism disorders, oxidative stress and inflammatory response challenged by palmitic acid plus oleic acid were obviously alleviated through activation of AMP-activated protein kinase signal with AMP-activated protein kinase activator AICAR in hepatocytes. In addition, we found that the beneficial effects of AMP-activated protein kinase signal in relieving lipid metabolism disorders, oxidative stress and inflammatory response are achieved by activating the nuclear factor erythroid 2-related factor 2 (NRF-2)/kelch-like ECH-associated protein 1 (KEAP1) pathway and inhibiting the NF-κB pathway in PO-stimulated primary chicken hepatocytes. Collectively, our data demonstrated that AMP-activated protein kinase acts as a potential target for the prevention of fatty liver hemorrhagic syndrome occurrence in laying hens.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Activated AMP-activated protein kinase prevents hepatic steatosis, oxidative stress and inflammation in primary chicken hepatocytes

Yao

Yang

et al. 2022

Front. Physiol.

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“…G protein-coupled estrogen receptor (GPER) has been shown to mediate rapid non-genomic estrogenic effects of estrogenic compounds (such as DHEA) [ 22 ]. Our recent and other researches also found that DHEA can activate GPER to perform its biological functions [ 20 , 23 , 24 ]. In addition, it has been reported that activated GPER can decrease the toll-like receptor 4 (TLR4)-mediated inflammation in murine macrophages and microglia [ 25 , 26 ]; and GPER agonist can inhibit the activation of NLRP3 inflammasomes [ 27 ].…”

Section: Introductionmentioning

confidence: 84%

Dehydroepiandrosterone exacerbates nigericin-induced abnormal autophagy and pyroptosis via GPER activation in LPS-primed macrophages

Cao

Yao

et al. 2022

Cell Death Dis

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As a widely acknowledged FDA-approved dietary supplement or over-the-counter medicines, dehydroepiandrosterone (DHEA) exerts anti-inflammatory and immunomodulatory function. Pyroptosis is an important form of programmed cell death (PCD), and which acts a key role in the body’s anti-infection and inflammatory responses. But the effects and mechanisms of DHEA on pyroptosis remain unclear. Here, we found that DHEA inhibited the NLRP3 inflammasome components expression by blocking inflammatory signals in lipopolysaccharide (LPS)-primed macrophages, and prevented the bacterial toxin nigericin (Nig)-induced NLRP3 inflammasome assembly. However, DHEA exacerbated NLRP3-independent cell death in Nig-treated inflammatory macrophages. During this process, DHEA induced the abnormal autophagy, which reflected as the blocking of autophagic flux and the accumulation of autophagy receptor p62 (SQSTM1) protein. In addition, DHEA caused a burst of reactive oxygen species (ROS) and activated extracellular signal-regulated kinase (ERK) phosphorylation in LPS plus Nig-stimulated macrophages but not in LPS-treated macrophages. Mechanistically, the present study certified that the activation of G protein-coupled estrogen receptor (GPER) signal mediated the cell death induced by DHEA in Nig-stimulated inflammatory macrophages, as GPER specific inhibitor G15 alleviated the abnormal autophagy and ultimately prevented the gasdermin D (GSDMD)-mediated pyroptosis induced by DHEA. Collectively, DHEA can exacerbate Nig-induced abnormal autophagy and pyroptosis via activation of GPER in LPS-primed macrophages, which prompts us the potential application value of DHEA in anti-infection or anti-tumor immunity.

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“…10 The activation of G proteincoupled estrogen receptor-mediated AMP-activated protein kinase (AMPK) signaling prevents the development of nonalcoholic steatohepatitis. 10 AMPK, known to induce eNOS, is activated through several physiological and pathological conditions, such as hypoxia, caloric restriction and physiological exercise but also via certain well-known pharmacological agents such as metformin, aspirin, canagliflozin, telmisartan and herbal substances such as resveratrol, berberine and quercetin. 11 Both mechanisms of action, either via S1Rinduced or AMPK-mediated eNOS activation, increase NO bioavailability and mechanistically support specific and immediate anti-SARS-CoV-2 effects.…”

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confidence: 99%

“…8,9 An additional mode of action for DHEA by its biotransformation into estrogen is upregulation of G protein-coupled estrogen receptor expression, a nonclassic estrogen receptor. 10 The activation of G proteincoupled estrogen receptor-mediated AMP-activated protein kinase (AMPK) signaling prevents the development of nonalcoholic steatohepatitis. 10 AMPK, known to induce eNOS, is activated through several physiological and pathological conditions, such as hypoxia, caloric restriction and physiological exercise but also via certain well-known pharmacological agents such as metformin, aspirin, canagliflozin, telmisartan and herbal substances such as resveratrol, berberine and quercetin.…”

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confidence: 99%

Anti-SARS-CoV-2 Action of 5α-Reductase Inhibitors May Be Mediated by Dehydroepiandrosterone. Letter.

Papadopoulos

Papadopoulou²,

Sutheesophon

et al. 2022

Journal of Urology

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We read with interest the study of Lyon et al. 1 5α-reductase inhibitor (5ARIs)-induced testosterone (T) and androstenedione (A4) increase may shunt these precursors to estrogens.Additional precursor steroids maybe involved and more plausibly account for the observation of reduction in community acquired severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. 1 Dutasteride decreases the formation of T, dihydrotestosterone (DHT) and precursor steroids in the backdoor pathway but increases steroid precursors, including dehydroepiandrosterone (DHEA), in the classical steroidogenesis pathway while finasteride despite a significant decrease in the non-sulfated DHEA leads to an accumulation of DHEA-Sulfate (DHEAS) in rats. 2,3 In post-finasteride patients, DHEA is increased both in plasma and central nervous system. 4 Both DHEA/DHEAS are moderate endogenous sigma 1 receptor (S1R) agonists (DHEA (Ki = 2.96 µM), DHEAS (Ki = 15.13 µM)), and similarly to the potent exogenous agonist fluvoxamine (Ki= 36nM), DHEA treatments may engender anti-SARS-CoV-2 protection through their S1Rmedated cardioprotective properties. 5,6 DHEA administration ameliorates pressure overloadinduced and transverse aortic constriction-induced cardiac hypertrophy and contractile dysfunction by upregulation of the S1R protein levels and activation the p-Akt-endothelial nitric

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The sex steroid precursor dehydroepiandrosterone prevents nonalcoholic steatohepatitis by activating the AMPK pathway mediated by GPR30

Cited by 20 publications

References 48 publications

Activated AMP-activated protein kinase prevents hepatic steatosis, oxidative stress and inflammation in primary chicken hepatocytes

Activated AMP-activated protein kinase prevents hepatic steatosis, oxidative stress and inflammation in primary chicken hepatocytes

Dehydroepiandrosterone exacerbates nigericin-induced abnormal autophagy and pyroptosis via GPER activation in LPS-primed macrophages

Anti-SARS-CoV-2 Action of 5α-Reductase Inhibitors May Be Mediated by Dehydroepiandrosterone. Letter.

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