Chemical hypoxia induces pro-inflammatory signals in fat-laden hepatocytes and contributes to cellular crosstalk with Kupffer cells through extracellular vesicles

Hernández, Alejandra; Geng, Yana; Sepúlveda, Rolando; Solı́s, Nancy; Torres, Javiera; Arab, Juan Pablo; Barrera, Francisco; Cabrera, Daniel; Moshage, Han; Arrese, Marco

doi:10.1016/j.bbadis.2020.165753

Cited by 35 publications

(21 citation statements)

References 67 publications

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“…A novel HIF-1α-induced eotaxin pathway identifies an unknown connection between hypoxia and the regulation of the severity of inflammation regulated by TLR4 in asthma ( 39 ). Hypoxia and elevated HIF-1α promotes inflammatory signals, including NLRP3/inflammasome/caspase-1 activation in fat-laden hepatocytes ( 40 ). In the present study, the effect of TMP on HIF-1α was examined under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF‑1α and apoptosis

Sun

Wang

et al. 2020

Mol Med Rep

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The aim of the present study was to investigate the protective effect and underlying mechanism of tetramethylpyrazine (TMP) on renal ischemia reperfusion injury (RIRI) in rats, which refers to the injury caused by the restoration of blood supply and reperfusion of the kidney after a period of ischemia. Sprague-Dawley rats were randomly divided into a Sham group, renal ischemia-reperfusion (I/R) group and TMP group. TMP hydrochloride (40 mg/kg, 6 h intervals) was given via intraperitoneal injection immediately after reperfusion in the TMP group, after 24 h the kidney tissues were taken for follow-up experiments. Pathological changes in the kidney tissues were observed by periodic acid-Schiff staining. Renal function was assessed by measuring levels of serum creatinine and blood urea nitrogen, and inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. Renal cell apoptosis was detected by TUNEL-DAPI double staining, mRNA and protein changes were analyzed by reverse transcription-quantitative PCR and western blotting. Cell viability was measured using a CCK-8 assay. It was found that the renal tissues of the sham operation group were notably abnormal, and the renal tissues of the I/R group were damaged, while the renal tissues of the TMP group were less damaged compared with those of the I/R group. Compared with the I/R group, the serum creatinine and blood urea nitrogen levels in the TMP group were low (all P<0.05), levels of inflammatory cytokines TNF-α and IL-6 decreased, the apoptotic rate was low (all P<0.05), and the relative expression levels of nucleotide-oligomerization domain-like receptor 3 (NLRP3) protein and mRNA in renal tissues were low (all P<0.05). The expression levels of hypoxia-inducible factor 1-α and NLRP3 increased after oxygen and glucose deprivation (OGD), and reduced after treatment with OGD and TMP (all P<0.05). It was concluded that TMP can reduce renal injury and improve renal function in RIRI rats, and its mechanism may be related to the reduction of NLRP3 expression in renal tissues.

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Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF‑1α and apoptosis

Sun

Wang

et al. 2020

Mol Med Rep

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“…Such changes might further aggravate metabolic diseases such as NAFLD, 62 aggravating NAFLD progression 54,63 . From a clinical point of view, specific abnormalities of bile duct chemistry are rare in COVID‐19‐infected patients 9 and, thus, the ACE2‐mediated liver injury could be mainly secondary to the localization of these receptors in the endothelial cells 17 and NAFLD progression might include exaggerated production of ROS and NO derivatives, 64 inflammatory pathways leading to cellular crosstalk with Kupffer cells 65 and HIF‐2α upregulation, 66 through suppression of fatty acid β‐oxidation and induction of lipogenesis in the liver via PPARα 63 . This hypothesis is partly supported by liver histology from patients deceased due to severe COVID‐19, reporting moderate microvesicular steatosis and mild lobular and portal activity, possibly due to a direct effect of SARS‐CoV‐2 infection or to drug‐induced liver injury (DILI) 67 …”

Section: Covid‐19 and Nafldmentioning

confidence: 99%

COVID‐19 and non‐alcoholic fatty liver disease: Two intersecting pandemics

Portincasa

Krawczyk

Smyk

et al. 2020

Eur J Clin Investigation

114

118

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Background: Initial evidence from China suggests that most vulnerable subjects to COVID-19 infection suffer from pre-existing illness, including metabolic abnormalities. The pandemic characteristics and high-lethality rate of COVID-19 infection have raised concerns about interactions between virus pathobiology and components of the metabolic syndrome. Methods: We harmonized the information from the recent existing literature on COVID-19 acute pandemic and mechanisms of damage in non-alcoholic fatty liver disease (NAFLD), as an example of chronic (non-communicable) metabolic pandemic. Results: COVID-19-infected patients are more fragile with underlying metabolic illness, including hypertension, cardiovascular disease, type 2 diabetes, chronic lung diseases (e.g. asthma, chronic obstructive pulmonary disease and emphysema) and metabolic syndrome. During metabolic abnormalities, expansion of metabolically active fat ('overfat condition') parallels chronic inflammatory changes, development of insulin resistance and accumulation of fat in configuring NAFLD. The deleterious interplay of inflammatory pathways chronically active in NAFLD and acutely in COVID-19-infected patients, can explain liver damage in a subgroup of patients and might condition a worse outcome in metabolically compromised NAFLD patients. In a subgroup of patients with NAFLD, the underlying liver fibrosis might represent an additional and independent risk factor for severe COVID-19 illness, irrespective of metabolic comorbidities. Conclusions: NAFLD can play a role in the outcome of COVID-19 illness due to frequent association with comorbidities. Initial evidences suggest that increased liver fibrosis in NAFLD might affect COVID-19 outcome. In addition, long-term monitoring of post-COVID-19 NAFLD patients is advisable, to document further deterioration of liver damage. Further studies are required in this field.

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“…EVs can contain a wide variety of cargoes [e.g., proteins, lipids, and nucleic acids [coding and noncoding RNA] and mitochondrial DNA] that mediate intercellular communication. In the setting of liver damage, hepatocytes increase EV release, which may act on different target cells leading to pivotal pathobiological processes, such as activation of macrophages, endothelial cells, and HSCs, thus promoting proinflammatory, angiogenic, and fibrotic responses (155)(156)(157)(158). Observations made in mouse models suggest that these EVmediated processes are relevant events in the pathogenesis of both NAFLD and ALD (159)(160)(161).…”

Section: Extracellular Vesicles and Micrornasmentioning

confidence: 99%

Non-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities

et al. 2020

Self Cite

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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, with a prevalence of 25-30%. Since its first description in 1980, NAFLD has been conceived as a different entity from alcohol-related fatty liver disease (ALD), despite that, both diseases have an overlap in the pathophysiology, share genetic-epigenetic factors, and frequently coexist. Both entities are characterized by a broad spectrum of histological features ranging from isolated steatosis to steatohepatitis and cirrhosis. Distinction between NAFLD and ALD is based on the amount of consumed alcohol, which has been arbitrarily established. In this context, a proposal of positive criteria for NAFLD diagnosis not considering exclusion of alcohol consumption as a prerequisite criterion for diagnosis had emerged, recognizing the possibility of a dual etiology of fatty liver in some individuals. The impact of moderate alcohol use on the severity of NAFLD is ill-defined. Some studies suggest protective effects in moderate doses, but current evidence shows that there is no safe threshold for alcohol consumption for NAFLD. In fact, given the synergistic effect between alcohol consumption, obesity, and metabolic dysfunction, it is likely that alcohol use serves as a significant risk factor for the progression of liver disease in NAFLD and metabolic syndrome. This also affects the incidence of hepatocellular carcinoma. In this review, we summarize the overlapping pathophysiology of NAFLD and ALD, the current data on alcohol consumption in patients with NAFLD, and the effects of metabolic dysfunction and overweight in ALD.

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Chemical hypoxia induces pro-inflammatory signals in fat-laden hepatocytes and contributes to cellular crosstalk with Kupffer cells through extracellular vesicles

Cited by 35 publications

References 67 publications

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF‑1α and apoptosis

Tetramethylpyrazine alleviates acute kidney injury by inhibiting NLRP3/HIF‑1α and apoptosis

COVID‐19 and non‐alcoholic fatty liver disease: Two intersecting pandemics

Non-alcoholic Fatty Liver Disease and Alcohol-Related Liver Disease: Two Intertwined Entities

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