Acrolein Is a Pathogenic Mediator of Alcoholic Liver Disease and the Scavenger Hydralazine Is Protective in Mice

Chen, Wei-Yang; Zhang, Jingwen; Ghare, Smita; Barve, Shirish; McClain, Craig J.; Joshi‐Barve, Swati

doi:10.1016/j.jcmgh.2016.05.010

Cited by 51 publications

(48 citation statements)

References 46 publications

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“…The hepatocyte exhibited loss of their normal architecture, intense cytoplasmic vacuolation, necrosis and hepatic steatosis. In fact, increased lipid peroxidation and depressed antioxidant status in the liver of rats receiving IMI caused oxidative stress which is known to induce endoplasmic reticulum (ER) stress [23]. Hepatic ER stress is accompanied by steatosis conforming to literature [24].…”

Section: Discussionsupporting

confidence: 76%

Imidacloprid enhances liver damage in Wistar rats: Biochemical, oxidative damage and histological assessment

Chakroun¹,

Grissa²,

Ezzi³

et al. 2017

JCLM

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Section: Discussionsupporting

confidence: 76%

Imidacloprid enhances liver damage in Wistar rats: Biochemical, oxidative damage and histological assessment

Chakroun¹,

Grissa²,

Ezzi³

et al. 2017

JCLM

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“…22 Acrolein was shown to induce protein adduct formation, and to mimic ethanol-induced ATF4/CHOP activation and cell death in cultured hepatocytes. 23 We found here that acrolein alone or in combination with ethanol dose-dependently induces acinar cell death, associated with XBP1s downregulation and CHOP upregulation (Supplementary Figure 6). Independently, a previous study showed that the CSE component hydroquinone causes apoptosis in retinal cells by upregulating CHOP and supressing XBP1s.…”

Section: Resultsmentioning

confidence: 64%

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

Lugea

Gerloff

et al. 2017

Gastroenterology

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Background & Aims Smoking, an independent risk factor for pancreatitis, accelerates the development of alcoholic pancreatitis. Alcohol feeding of mice induces upregulation of spliced X-box binding protein 1 (XBP1s), which regulates the endoplasmic reticulum (ER) unfolded protein response and promotes cell survival upon ER stress. We examined whether smoking affects the adaptive mechanisms induced by alcohol and accelerates disorders of the ER in pancreatic acinar cells. Methods We studied the combined effects of ethanol and cigarette smoke extract (CSE) on ER-stress and cell death responses in mouse and human primary acini and the acinar cell line AR42J. Cells were incubated with ethanol (EtOH, 50 mM), CSE (20–40 μg/ml), or both (CSE+EtOH), and analyzed by immunoblotting, quantitative reverse transcription PCR, and cell death assays. Some cells were incubated with MKC-3946, an inhibitor of endoplasmic reticulum to nucleus signaling 1 (ERN1, also called IRE1) that blocks XBP1s formation. Male Sprague-Dawley rats were fed isocaloric amounts of an ethanol-containing (Lieber-DeCarli) or control diet for 11 weeks and exposed to cigarette smoke or room air in an exposure chamber for 2 hours each day. During the last 3 weeks, a subset of rats received intravenous injections of lipopolysaccharide (LPS, 3 mg/kg per weeks) to induce pancreatitis or saline (control). Pancreatic tissues were collected and analyzed by histology and immunostaining techniques. Results In AR42J and primary acini, CSE+EtOH induced cell death (necrosis and apoptosis), but neither agent alone had this effect. Cell death was associated with a significant decrease in expression of XBP1s. CSE+EtOH, but neither agent alone, slightly decreased ATP levels in AR42J cells, but induced oxidative stress and sustained activation (phosphorylation) of eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK) and increased protein levels of DNA damage inducible transcript 3 (DDIT3, also called CHOP). CHOP regulates transcription to promote apoptosis. Incubation of AR42J or primary mouse or human acinar cells with MKC-3946 reduced expression of XBP1s, increased levels of CHOP and induced cell death. In rats fed ethanol diet, exposure to cigarette smoke increased ER stress in acinar cells and sensitized the pancreas to LPS-induced pathology. Conclusions Cigarette smoke promotes cell death and features of pancreatitis in ethanol-sensitized acinar cells by suppressing the adaptive unfolded protein response signaling pathway. It also activates ER stress pathways that promote acinar cell death.

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“…Concurrently, elevated acrolein staining correlates with the increased expression of GSTπ. GSTπ has been reported to metabolize acrolein and in a cell culture model, transfection of catalytically inactive GSTπ resulted in enhanced production of lipid peroxidation products as well 51,52 . In addition to effects on lipid peroxidation, polymorphisms in GSTπ are risk factors for NAFLD and decreased GSTπ expression are associated with carcinogenesis 53 .…”

Section: Discussionmentioning

confidence: 99%

“…In the biliary disorder primary biliary cholangitis (PBC), GSTπ expression is decreased suggesting that GSTπ modulation is disease dependent. GSTπ has been reported to contribute to detoxification of reactive aldehydes in other hepatic diseases which overall suggests that the upregulation of GSTπ in end stage NASH samples is an attempt to mitigate damage that is occurring due to lipid peroxidation/protein carbonylation 52 .…”

Section: Discussionmentioning

confidence: 99%

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

Shearn

Saba

Roede

et al. 2017

Free Radical Biology and Medicine

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Objective In the liver, a contributing factor in the pathogenesis of non-alcoholic fatty liver disease is oxidative stress leading to the accumulation of highly reactive electrophilic α/β unsaturated aldehydes. The objective of this study was to determine if significant differences were evident when evaluating carbonylation in human end-stage fatty nonalcoholic steatohepatitis (fNASH) compared to end-stage nonfatty NASH (nfNASH). Methods Using hepatic tissue obtained from healthy humans and patients diagnosed with end stage nfNASH or fNASH, overall carbonylation was assessed by immunohistochemistry (IHC) and LC-MS/MS followed by bioinformatics. Results Picrosirius red staining revealed extensive fibrosis in both fNASH and nfNASH which corresponded with increased reactive aldehyde staining. Although significantly elevated when compared to normal hepatic tissue, no significant differences in overall carbonylation and fibrosis were evident when comparing fNASH with nfNASH. Examining proteins that are critical for anti-oxidant defense revealed elevated expression of thioredoxin, thioredoxin interacting protein, glutathione S-transferase p1 and mitochondrial superoxide dismutase in human NASH. As important, using immunohistochemistry, significant colocalization of the aforementioned proteins occurred in cytokeratin 7 positive cells indicating that they are part of the ductular reaction. Expression of catalase and Hsp70 decreased in both groups when compared to normal human liver. Mass spectrometric analysis revealed a total of 778 carbonylated proteins. Of these, 194 were common to all groups, 124 unique to tissue prepared from healthy individuals, 357 proteins exclusive to NASH, 124 proteins distinct to samples from patients with fNASH and 178 unique to nfNASH. Using functional enrichment analysis of hepatic carbonylated proteins revealed a propensity for increased carbonylation of proteins regulating cholesterol and Huntington’s disease related pathways occurred in nfNASH. Examining fNASH, increased carbonylation was evident in proteins regulating Rho cytoskeletal pathways, nicotinic acetylcholine receptor signaling and chemokine/cytokine inflammatory pathways. Using LC-MS/MS analysis and trypsin digests, sites of carbonylation were identified on peptides isolated from vimentin, endoplasmin and serum albumin in nfNASH and fNASH respectively. Conclusions These results indicate that cellular factors regulating mechanisms of protein carbonylation may be different depending on pathological diagnosis of NASH. Furthermore these studies are the first to use LC-MS/MS analysis of carbonylated proteins in human NAFLD and explore possible mechanistic links with end stage cirrhosis due to fatty liver disease and the generation of reactive aldehydes.

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Acrolein Is a Pathogenic Mediator of Alcoholic Liver Disease and the Scavenger Hydralazine Is Protective in Mice

Cited by 51 publications

References 46 publications

Imidacloprid enhances liver damage in Wistar rats: Biochemical, oxidative damage and histological assessment

Imidacloprid enhances liver damage in Wistar rats: Biochemical, oxidative damage and histological assessment

The Combination of Alcohol and Cigarette Smoke Induces Endoplasmic Reticulum Stress and Cell Death in Pancreatic Acinar Cells

Differential carbonylation of proteins in end-stage human fatty and nonfatty NASH

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