Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers

Anavi, Sarit; Madar, Zecharia; Tirosh, Oren

doi:10.1016/j.redox.2017.06.008

Cited by 31 publications

(27 citation statements)

References 93 publications

(152 reference statements)

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“…On the other hand, NAFLD has the potential to progress through the inflammatory phase of NASH to fibrosis, cirrhosis, and, in some cases, liver failure or HCC [ 3 ]. The disease etiology also involves significant redox and oxidative stress components [ 4 – 7 ].…”

Section: Nonalcoholic Fatty Liver Disease (Nafld) and Lipotoxicitymentioning

confidence: 99%

Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

Tirosh

2018

Oxidative Medicine and Cellular Longevity

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Cholesterol is the only lipid whose absorption in the gastrointestinal tract is limited by gate-keeping transporters and efflux mechanisms, preventing its rapid absorption and accumulation in the liver and blood vessels. In this review, I explored the current data regarding cholesterol accumulation in liver cells and key mechanisms in cholesterol-induced fatty liver disease associated with the activation of deleterious hypoxic and nitric oxide signal transduction pathways. Although nonalcoholic fatty liver disease (NAFLD) affects both obese and nonobese individuals, the mechanism of NAFLD progression in lean individuals with healthy metabolism is puzzling. Lean NAFLD individuals exhibit normal metabolic responses, implying that liver damage is not associated with impaired metabolism per se and that direct lipotoxic effects are crucial for disease progression. Several redox and oxidant signaling pathways involving cholesterol are at play in fatty liver disease development. These include impairment of the mitochondrial and lysosomal function by cholesterol loading of the inner-cell membranes; formation of cholesterol crystals and hepatocyte degradation; and crown-like structures surrounding degrading hepatocytes, activating Kupffer cells, and evoking inflammation. The current review focuses on the induction of liver inflammation, fibrosis, and steatosis by free cholesterol via the hypoxia-inducible factor 1α (HIF-1α), a main oxygen-sensing transcription factor involved in all stages of NAFLD. Cholesterol loading in hepatocytes can result in chronic HIF-1α activity because of the decreased oxygen availability and excessive production of nitric oxide and mitochondrial reactive oxygen species.

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Section: Nonalcoholic Fatty Liver Disease (Nafld) and Lipotoxicitymentioning

confidence: 99%

Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

Tirosh

2018

Oxidative Medicine and Cellular Longevity

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“…nos. C1158 and C1115; Beyotime Institute of Biotechnology) according to the manufacturer's protocols (43). SW837 cells underwent TUNEL staining and caspase-3/9 activity assays.…”

Section: Measurement Of Lactate Production Glucose Upta�e and Mito-mentioning

confidence: 99%

Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin‑mediated mitophagy by suppressing AMPK/Skp2 pathways

Ke-bo

2018

Mol Med Report

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Mitophagy is important for cancer development. Notably, the role of Parkin‑mediated mitophagy in colorectal cancer (CRC) mortality has not been fully determined. Therefore, the present study aimed to investigate the effect of Parkin‑mediated mitophagy on CRC apoptosis. In addition, the present study investigated the therapeutic effects of Tanshinone IIA (Tan IIA) on the regulation of CRC cell death via mitophagy. Cellular apoptosis was measured following Tan IIA treatment. In addition, mitophagy activity was evaluated by immunofluorescence and western blotting. The results of the present study revealed that Tan IIA may enhance CRC cell death. In addition, the results demonstrated that Tan IIA enhanced mitochondrial apoptosis, as demonstrated by reduced mitochondrial membrane potential, elevated mitochondrial permeability transition pore opening, and increased oxidative stress, mitochondrial energy disorder and proapoptotic factor expression. Furthermore, the results of the present study demonstrated that Tan IIA induced mitochondrial apoptosis via inhibition of mitophagy. In addition, it was revealed that mitophagy could suppress mitochondrial apoptosis. Functional assays revealed that Tan IIA suppressed the adenosine monophosphate‑activated protein kinase (AMPK) pathway, resulting in the inactivation of S‑phase kinase associated protein 2 (Skp2). Furthermore, reduced levels of Skp2 failed to activate Parkin, thus resulting in inhibition of mitophagy. Conversely, reactivation of AMPK and overexpression of Skp2 rescued mitophagy activity and thus attenuated the Tan IIA‑induced apoptosis of CRC cells. In conclusion, the results of the present study demonstrated the beneficial role of mitophagy in CRC cell survival and suggested that Tan IIA may be an effective therapeutic agent, which suppresses mitophagy activity and enhances CRC apoptosis.

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“…Hyperglycemia induces reactive oxygen species (ROS) accumulation that, in turn, induces endothelial dysfunction and cellular damage. Human serum albumin (HSA) is a major protein in the blood circulation, and the redox status of its thiol (SH) group plays the predominant role in redox regulation 15,16 , and it may accurately reveal oxidative stress and can act as a potential biomarker of oxidative stress and prognostic biomarker of diabetes 17 . Under physiological conditions, Cys34 of HSA exists in either the reduced or oxidized form.…”

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Serum albumin cysteine trioxidation is a potential oxidative stress biomarker of type 2 diabetes mellitus

Paramasivan

Adav

Ngan

et al. 2020

Sci Rep

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Metabolic disorders in T2DM generate multiple sources of free radicals and oxidative stress that accelerate nonenzymatic degenerative protein modifications (DPMs) such as protein oxidation, disrupt redox signaling and physiological function, and remain a major risk factor for clinical diabetic vascular complications. in order to identify potential oxidative biomarkers in the blood plasma of patients with T2DM, we used LC-MS/MS-based proteomics to profile plasma samples from patients with T2DM and healthy controls. The results showed that human serum albumin (HSA) is damaged by irreversible cysteine trioxidation, which can be a potential oxidative stress biomarker for the early diagnosis of T2DM. The quantitative detection of site-specific thiol trioxidation is technically challenging; thus, we developed a sensitive and selective LC-MS/MS workflow that has been used to discover and quantify three unique thiol-trioxidized HSA peptides, ALVLIAFAQYLQQC (SO3H) PFEDHVK (m/z 1241.13), YIC (SO3H) ENQDSISSK (m/z 717.80) and RPC (SO3H) FSALEVDETYVPK (m/z 951.45), in 16 individual samples of healthy controls (n = 8) and individuals with diabetes (n = 8). Targeted quantitative analysis using multiple reaction monitoring mass spectrometry revealed impairment of the peptides with m/z 1241.13, m/z 717.80 and m/z 951.45, with significance (P < 0.02, P < 0.002 and P < 0.03), in individuals with diabetes. the results demonstrated that a set of three HSA thiol-trioxidized peptides, which are irreversibly oxidatively damaged in HSA in the plasma of patients with T2DM, can be important indicators and potential biomarkers of oxidative stress in T2DM.open Scientific RepoRtS | (2020) 10:6475 | https://doi.org/10.1038/s41598-020-62341-zwww.nature.com/scientificreports www.nature.com/scientificreports/ neuropathy and retinopathy 5 . However, measuring oxidative stress is challenging since reactive oxygen species (ROS) or other metabolic products are extremely unstable; hence, the gold standard to measure oxidative stress has not yet been established. As oxidative stress is a potential indicator to predict diabetes progression and is also beneficial for longitudinal follow-up to evaluate the response to treatment, there remains an unmet need to develop a reliable biomarker that can be used to estimate oxidative stress quantitatively.Modified proteins are prospective biomarkers for both diagnoses and assessment of disease treatment; hence, the American Diabetes Association 6 and the World Health Organization 7 approved the use of glycated hemoglobin A1c (HbA1c) in diagnosing DM. Modified proteins such as plasma glycoproteins including human epidermal growth factor receptor 2 (HER2) in breast cancer, prostate-specific antigen (PSA) in prostate cancer, carcinoembryonic antigen (CEA) in colorectal cancer, cancer antigen 125 (CA-125) in ovarian cancer, alpha-fetoprotein in hepatocellular carcinoma have been approved by the Food and Drug Administration (FDA) as a potential diagnostic biomarker of various cancers 8 . Further, the role of DPMs, su...

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Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers

Cited by 31 publications

References 93 publications

Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

Tanshinone IIA regulates colorectal cancer apoptosis via attenuation of Parkin‑mediated mitophagy by suppressing AMPK/Skp2 pathways

Serum albumin cysteine trioxidation is a potential oxidative stress biomarker of type 2 diabetes mellitus

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