Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice

Zhang, Wenliang; Zhong, Wei; Sun, Qian; Sun, Xinguo; Zhou, Zhanxiang

doi:10.1038/s41598-017-02759-0

Cited by 39 publications

(38 citation statements)

References 42 publications

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“…These studies show that HP can change one class of oxylipin (prostaglandins) in the kidney that could exert adverse effects on kidney. Liver is the key site of protein metabolism and liver and blood oxylipins have been associated with a number of diseased liver conditions and other disorders [22][23][24][25][26][27][28], but these also have not been examined in the context of HP diets.…”

Section: List Of Abbreviationsmentioning

confidence: 99%

“…Some LA derived oxylipins in serum are associated with pain and Achilles tendinopathy [28,155], and lower levels of 13-HODE have been reported in colon and lung cancer [156,157]. Oxylipins in liver and blood have been associated with a number of diseased liver conditions and other disorders [22][23][24][25][26][27][28], but these have not been examined in the context of HP diets.…”

Section: Oxylipins In Kidney Liver and Serummentioning

confidence: 99%

“…It is well accepted that healthy lifestyle changes focused primarily on weight loss are the first-line approach to obesity but the optimal diet to attain this is not clear. A popular approach to weight loss is to use HP diets but there is insufficient information on the benefits and risks of HP [22][23][24][25][26][27][28], but these also have not been examined in the context of HP diets. In this study, livers were taken since they are the main site for protein metabolism and blood was taken as a possible tissue to be used to reflect changes in the kidney and/or liver.…”

Section: Rationalementioning

confidence: 99%

“…Additionally, LA derived oxylipins such as EpOME and DiHOME appear to be cytotoxic in renal and other cells, but whether they are altered in tissues with HP feeding is unknown [147,[149][150][151][152]. Similarly, liver and blood oxylipins have been associated with a number of diseased liver conditions and other disorders [22][23][24][25][26][27][28], but these also have not been examined in the context of HP diets.…”

Section: Introductionmentioning

confidence: 99%

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Linoleic acid derived oxylipins are elevated in kidney and liver and reduced in serum in rats given a high-protein diet

Islam

Ravandi

Aukema

2018

The Journal of Nutritional Biochemistry

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High protein (HP) diets are often used as a means to reduce obesity, but their long-term effects remain unclear. In vitro studies suggest the involvement of a subset of oxylipins in the tissue response to HP diets. To examine the role of these bioactive lipids in vivo, normal adult male Sprague Dawley rats were provided isocaloric diets with LP (low protein, 8% protein by weight), NP (normal protein, 14%) or HP (50%) diets for 2 weeks, and targeted lipidomic analysis of oxylipins in kidney (cortex and medulla), liver and serum was performed by HPLC-MS/MS. The main group of oxylipins affected by the HP diet was the oxylipins derived from linoleic acid (LA), many of which were elevated in kidney (particularly the medulla) and liver, but reduced in serum of rats provided the HP compared to NP or LP diets. A smaller proportion of other n-6 fatty acid derived oxylipins were lower in kidney and higher in liver, and none were affected in serum, by HP feeding. Few n-3 oxylipins were affected by protein level. In liver only, the oxylipin product to substrate ratios of the soluble epoxide hydrolase enzyme were higher in LP fed rats. Differences between cortex and medulla oxylipins suggest relatively higher cortex activity of 5- and 8-lipoxygenase and cytochrome P450 hydroxylase, and higher medulla cyclooxygenase and 12- and 15-lipoxygenase activity. Further studies are needed to elucidate the physiological effects of the changes in these novel oxylipins in response to short-term dietary HP.

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Section: List Of Abbreviationsmentioning

confidence: 99%

Section: Oxylipins In Kidney Liver and Serummentioning

confidence: 99%

Section: Rationalementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Linoleic acid derived oxylipins are elevated in kidney and liver and reduced in serum in rats given a high-protein diet

Islam

Ravandi

Aukema

2018

The Journal of Nutritional Biochemistry

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“…The expression of ALOX12 and ALOX15 (mRNA and protein levels) and COX2 was upregulated in ρ 0 cells (Figure ). ALOX15 produces 13‐hydroxyoctadecadienoic acid, which is a precursor of HNE from linoleic acid . Inhibition of ALOX 12 and 15, unlike ALOX5, resulted in the downregulation of HNE and H 2 O 2 permeability in ρ 0 cells (Figure ).…”

Section: Discussionmentioning

confidence: 95%

Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNA

et al. 2019

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4‐Hydroxynonenal (HNE) is an important product of plasma membrane lipid peroxidation, which is a cause of cell and tissue injury. Mitochondrial DNA (mtDNA)‐depleted ρ0 cells were established using human cervical cancer and oral squamous cell carcinoma cell lines. We investigated the effect of reactive oxygen species in ρ0 cells, especially the mechanism of hydrogen peroxide (H2O2)‐mediated cell death. These cell were subjected to high oxidative stress and, compared with their parental cells, showed greater sensitivity to H2O2 and high lipid peroxidation. Upregulation of HNE in the plasma membrane was observed prior to the increase in intracellular H2O2. The amount of oxidized lipid present changed H2O2 permeability and administration of oxidized lipid led to further cell death after treatment with H2O2. Expression levels of lipoxygenase ALOX genes (ie ALOX5, ALOX12, and ALOX15) were upregulated in ρ0 cells, as were expression levels of ALOX12 and ALOX15 proteins. ALOX5 protein was mainly distributed in the nucleus, while ALOX12 and ALOX15 proteins were distributed in the nucleus and the cytoplasm. Although expression of COX2 gene was upregulated, its protein expression did not increase. ALOX (especially ALOX15) may be involved in the sensitivity of cancer cells to treatment. These data offer promise for the development of novel anticancer agents by altering the oxidation state of the plasma membrane. Our results showed that lipid peroxidation status is important for H2O2 sensitivity and that ALOX15 is involved in lipid peroxidation status.

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Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease

et al. 2020

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Background and Aims Alcohol‐associated liver disease (ALD) is a common chronic liver disease worldwide with high morbidity and mortality, and no Food and Drug Administration–approved therapies. Fructose (dietary or endogenous), its metabolite uric acid, and aldose reductase (AR, the only endogenous enzyme that produces fructose) are strongly associated with the development of nonalcoholic fatty liver disease. However, the role of AR or its metabolites in ALD remains understudied and was examined using human specimens, cultured cells, and mouse model systems. Approach and Results We demonstrated in liver specimens from patients with alcoholic hepatitis, the AR up‐regulation and elevated AR metabolites (sorbitol, fructose, and uric acid), which correlated significantly with (1) increased lipid peroxidation byproducts and endoplasmic reticulum (ER) stress, (2) decreased protective ER chaperones, and (3) greater cell death and liver injury. Furthermore, we established a causal role for AR in ALD by showing that the genetic deficiency of AR (knockout mice) prevented alcohol‐induced increase in harmful AR metabolites, toxic aldehydes, steatosis, ER stress, apoptosis, and liver injury. Finally, we demonstrated the therapeutic potential of pharmacological AR inhibition against alcohol‐induced hepatic injury in experimental ALD. Conclusions Our data demonstrate that hepatic AR up‐regulation, and consequent elevation in fructose, sorbitol and/or uric acid, are important factors contributing to alcohol‐induced steatosis, ER stress, apoptosis, and liver injury in both experimental and human ALD. Our study provides a strong rationale to evaluate AR as a potential therapeutic target and to test AR inhibitors to ameliorate alcohol‐induced liver injury.

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Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice

Cited by 39 publications

References 42 publications

Linoleic acid derived oxylipins are elevated in kidney and liver and reduced in serum in rats given a high-protein diet

Linoleic acid derived oxylipins are elevated in kidney and liver and reduced in serum in rats given a high-protein diet

Lipid peroxidation increases hydrogen peroxide permeability leading to cell death in cancer cell lines that lack mtDNA

Elevated Fructose and Uric Acid Through Aldose Reductase Contribute to Experimental and Human Alcoholic Liver Disease

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