New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro

Park, Min-Jung; Kim, Dong-Il; Choi, Joo-Hee; Heo, Young-Ran; Park, Soo-Hyun

doi:10.1016/j.cellsig.2015.04.010

Cited by 140 publications

(116 citation statements)

References 46 publications

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“…Park et al . (2015) have shown that blocking the migration of PRMT3 to the nucleus using the myokine irisin also decreased the induction of lipogenesis via LXR. We therefore anticipate that in our in vivo setting, PRMT3 does not directly modulate LXR transcription or translation efficiency but rather serves like a selective LXR modulator that controls the transcription of a selected cluster of lipogenic LXR target genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

Nahon

Groeneveldt

Geerling

et al. 2018

British J Pharmacology

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Background and PurposeAgonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol‐driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by concomitant LXR‐induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co‐activator of LXR activity. Here, we verified the hypothesis that PRMT3 inhibition selectively disrupts the ability of LXR to stimulate lipogenesis while maintaining its capacity to modulate macrophage cholesterol homeostasis.Experimental ApproachA combination of the LXR agonist T0901317 and palm oil was administered to C57BL/6 mice to maximally stimulate LXR and PRMT3 activity. PRMT3 activity was inhibited using the allosteric inhibitor SGC707.Key ResultsTreatment with SGC707 did not negatively influence the T0901317/palm oil‐induced up‐regulation of the cholesterol efflux ATP‐binding cassette transporter genes, ABCA1 and ABCG1, in peritoneal cells. In contrast, SGC707 treatment was associated with a significant decrease in the hepatic expression of the lipogenic gene fatty acid synthase (−64%). A similar trend was observed for stearoyl‐coenzyme A desaturase and acetyl CoA carboxylase expression (−43%; −56%). This obstruction of lipogenic gene transcription coincided with a significant 2.3‐fold decrease in liver triglyceride content as compared with the T0901317 and palm oil‐treated control group.Conclusion and ImplicationsWe showed that inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR‐driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on macrophage cholesterol efflux pathways is maintained.

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Section: Discussionmentioning

confidence: 99%

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

Nahon

Groeneveldt

Geerling

et al. 2018

British J Pharmacology

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“…In this regard, the circulating levels of irisin were found to be altered in obese individuals and diabetic patients [8]; these levels were considered to be one biomarker for the prediction of the development of diabetes and mortality risk of cardiovascular diseases [9,10]. We and others have demonstrated that, in an overnutrition state, irisin can restore metabolic homeostasis, thereby alleviating insulin resistance and protecting cell function as well as survival in hepatic tissues [11][12][13]. For instance, irisin attenuated PA-induced excessive lipid accumulation in hepatocytes [13], while deficiency of FNDC5 exacerbated hepatic lipogenesis and lipid accumulation in obese mice [11].…”

Section: Introductionmentioning

confidence: 99%

“…We and others have demonstrated that, in an overnutrition state, irisin can restore metabolic homeostasis, thereby alleviating insulin resistance and protecting cell function as well as survival in hepatic tissues [11][12][13]. For instance, irisin attenuated PA-induced excessive lipid accumulation in hepatocytes [13], while deficiency of FNDC5 exacerbated hepatic lipogenesis and lipid accumulation in obese mice [11].…”

Section: Introductionmentioning

confidence: 99%

“…Activation of adenosine monophosphate-activated protein kinase (AMPK) is associated, at least partially, with the protective effects of irisin on lipid metabolism via regulation of the expression and activity of lipogenic factors, such as acetyl-CoA-carboxylase (ACC) and fatty acid synthase (FAS) [12,13]. AMPK is a highly evolutionarily conserved cellular energy status sensor that transmits metabolic stress signals and restores metabolic homeostasis by integrating physiological signals [14].…”

Section: Introductionmentioning

confidence: 99%

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Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

Zhang¹,

Xie²,

Leung³

2018

Cell Physiol Biochem

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Background/Aims: Islet metabolic disorder and inflammation contribute to the pathogenesis and progression of type 2 diabetes mellitus (T2DM). Irisin is a recently identified adipomyokine with protective effects on metabolic homeostasis and inflammation-suppressing effects in hepatic and vascular cells. The present study examined the effects of irisin on lipid metabolism and inflammation in β cells under glucolipotoxic conditions. Methods: Rat INS-1E β cells and islets isolated from C57BL/6 mice were incubated in glucolipotoxic conditions with or without irisin. Intracellular lipid contents and lipogenic gene expression were determined by enzymatic colorimetric assays and real-time PCR, respectively. Inflammatory status was evidenced by Western blot analysis for the phosphorylation of nuclear factor-κB (NF-κB) p65 and real-time PCR analysis for the expression of pro-inflammatory genes. Results: Irisin reversed glucolipotoxicity-induced intracellular non-esterified fatty acid (NEFA) and triglyceride accumulation, suppressed associated elevations in lipogenic gene expression, and phosphorylated acetyl-CoA-carboxylase (ACC) in INS-1E cells. These demonstrated effects were dependent on irisin-activated adenosine monophosphate-activated protein kinase (AMPK). Meanwhile, AMPK signaling mediated the protective effects of irisin on INS-1E cell insulin secretory ability and survival as well. Additionally, irisin inhibited phosphorylation of NF-κB p65 while decreasing the expression of pro-inflammatory genes in INS-1E cells under glucolipotoxic conditions. Moreover, irisin also improved insulin secretion, inhibited apoptosis, and restored β-cell function-related gene expression in isolated mouse islets under glucolipotoxic conditions. Conclusion: Irisin attenuated excessive lipogenesis in INS-1E cells under glucolipotoxic state through activation of AMPK. Irisin also suppressed overnutrition-induced inflammation in INS-1E cells. Our findings implicate irisin as a promising therapeutic target for the treatment of islet lipid metabolic disorder and islet inflammation in T2DM.

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“…To confirm the protective role of SF preparation in PA-induced AML12 injuries by inhibition of JNK pathway, it would be better to perform experiments in JNK deficient hepatocytes. Additionally, it was reported that activation of p38MAPK also contributed to NFκB activation and mitochondrial protein Cox-2 upregulation in PA-treated AML12 cells [32]. In rats, SF preparation protected hepatic tissue from ischemia-reperfusion injury by decreasing the ratio of thromboxane A (2) and prostacyclin, and increasing the activities of Na + /K + -ATPase and Ca + /Mg + -ATPase [33].…”

Section: Discussionmentioning

confidence: 99%

ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways

Ji¹,

Jiao

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nonalcoholic steatohepatitis includes steatosis along with liver inflammation, hepatocyte injury and fibrosis. In this study, we investigated the protective role and the potential mechanisms of a traditional Chinese medicine ShenFu (SF) preparation in an in vitro hepatic steatosis model. Methods: In palmitic acid (PA)-induced murine hepatic AML12 cell injury, effects of SF preparation on cellular apoptosis and intracellular triglyceride (iTG) level were assessed using TUNEL and TG Colorimetric Assay. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were measured using DCF and JC-1 assay. Cytokine levels were evaluated using ELISA assay. Immunoblot was used to compare the activation level of c-Jun N terminal kinase (JNK), NADPH oxidase (Nox4), and NFκB pathways. Results: Addition of SF preparation prevented PA-mediated increase of apoptosis and iTG as well as IL-8 and IL-6. In PA-treated cell, SF preparation reduced the level of Nox4 and ROS, while increasing the level of MMP and the expression of manganese superoxide dismutase (MnSOD) and catalase, indicating emendation of mitochondrial dysfunction. Nox4 inhibitor GKT137381 prevented PA-induced increase of ROS and apoptosis, while decreasing iTG slightly and not influencing the level of IL-8 and IL-6. SF preparation prevented PA-induced upregulation of phospho-JNK. JNK inhibitor SP600125 prevented PA-mediated increase of Nox4, IL-8, IL-6 and iTG. Nuclear translocation of NFκB/p65 was detected in PA-treated cells, which was prevented by SF preparation. An IκB degradation inhibitor, BAY11-7082, prevented PA-induced increase of IL-8 and IL-6 as well as iTG, whereas it only decreased ROS levels slightly and showed no influence on cellular apoptosis. Conclusion: SF preparation shows a beneficial role in prevention of hepatocyte injury by attenuating oxidative stress and cytokines production at least partially through inhibition of JNK/Nox4 and JNK/NFκB pathway, respectively.

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New role of irisin in hepatocytes: The protective effect of hepatic steatosis in vitro

Cited by 140 publications

References 46 publications

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

Irisin Ameliorates Glucolipotoxicity-Associated β-Cell Dysfunction and Apoptosis via AMPK Signaling and Anti-Inflammatory Actions

ShenFu Preparation Protects AML12 Cells Against Palmitic Acid-Induced Injury Through Inhibition of Both JNK/Nox4 and JNK/NFκB Pathways

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