Diet high in fructose promotes liver steatosis and hepatocyte apoptosis in C57BL/6J female mice: Role of disturbed lipid homeostasis and increased oxidative stress

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARα in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARα-null mice. Primary hepatocytes from wild-type but not PPARα-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARα-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARα, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARα-null mice. Of the 815 genes regulated by WY in wild-type mice (p≤ 0.001; ≥1.5-fold or ≤-1.5-fold), only two genes were regulated similarly by WY in PPARα-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARα controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

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Critical role of exposure time to endogenous oxidative stress in hepatocyte apoptosis

Redox Report ◽

10.1179/135100007x200362 ◽

2007 ◽

Vol 12 (6) ◽

pp. 275-281 ◽

Cited By ~ 10

Author(s):

Yasuhiro Ishihara ◽

Norio Shimamoto

Keyword(s):

Oxidative Stress ◽

Exposure Time ◽

Critical Role ◽

Hepatocyte Apoptosis

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Endogenous opioids modulate hepatocyte apoptosis in a rat model of chronic cholestasis: the role of oxidative stress

Liver International ◽

10.1111/j.1478-3231.2007.01457.x ◽

2007 ◽

Vol 27 (4) ◽

pp. 538-547 ◽

Cited By ~ 15

Author(s):

Seyedmehdi Payabvash ◽

Saman Kiumehr ◽

Behtash Ghazi Nezami ◽

Ali Zandieh ◽

Pasha Anvari ◽

...

Keyword(s):

Oxidative Stress ◽

Rat Model ◽

Endogenous Opioids ◽

Hepatocyte Apoptosis ◽

Chronic Cholestasis

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Evaluation of Biomarkers of NAFLD in a Cohort of Morbidly Obese Patients

Journal of Nutrition and Metabolism ◽

10.1155/2011/369168 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 17

Author(s):

Julia Kälsch ◽

Lars P. Bechmann ◽

Hagen Kälsch ◽

Martin Schlattjan ◽

Jochen Erhard ◽

...

Keyword(s):

Liver Steatosis ◽

Tunel Staining ◽

Morbidly Obese ◽

Surrogate Markers ◽

Obese Patients ◽

Review Of The Literature ◽

Hepatocyte Apoptosis ◽

Nonalcoholic Fatty Liver ◽

Sirius Red

Hepatocyte apoptosis is a key event in nonalcoholic fatty liver disease (NAFLD), and serum apoptotic markers are emerging as surrogate markers for NAFLD. We studied the role of caspase-cleaved cytokeratin18 in the diagnosis of fibrosis in a cohort of 127 morbidly obese patients and also performed a review of the literature biomarkers of NAFLD and fibrosis. Here, we found that cleaved caspase 18 correlated with liver steatosis and liver injury as assessed by serum transaminase levels. Furthermore, hepatocyte apoptosis as assessed by cleaved CK18 and TUNEL staining correlated with the extent of fibrosis as assessed by Sirius Red staining and serum hyaluronic acid. These results underscore the important role of hepatocyte apoptosis in the pathogenesis of fibrosis in NAFLD, which led to the utilization of surrogate markers for apoptosis in the noninvasive diagnosis of NAFLD. We furthermore reviewed current literature of biomarkers of NAFLD and fibrosis.

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The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7504521 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Qing Pang ◽

Hao Jin ◽

Xiquan Ke ◽

Zhongran Man ◽

Yong Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Injury ◽

Inflammatory Response ◽

Concanavalin A ◽

Serum Levels ◽

Hepatocyte Apoptosis ◽

Con A ◽

Serotonin 2A Receptor ◽

Serotonin 2A

Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.

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Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/9547613 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 126

Author(s):

Mario Masarone ◽

Valerio Rosato ◽

Marcello Dallio ◽

Antonietta Gerarda Gravina ◽

Andrea Aglitti ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Liver Steatosis ◽

Primary Role ◽

Nonalcoholic Fatty Liver ◽

Starting Point

Liver steatosis without alcohol consumption, namely, nonalcoholic fatty liver disease (NAFLD), is a common hepatic condition that encompasses a wide spectrum of presentations, ranging from simple accumulation of triglycerides in the hepatocytes without any liver damage to inflammation, necrosis, ballooning, and fibrosis (namely, nonalcoholic steatohepatitis) up to severe liver disease and eventually cirrhosis and/or hepatocellular carcinoma. The pathophysiology of fatty liver and its progression is influenced by multiple factors (environmental and genetics), in a “multiple parallel-hit model,” in which oxidative stress plays a very likely primary role as the starting point of the hepatic and extrahepatic damage. The aim of this review is to give a comprehensive insight on the present researches and findings on the role of oxidative stress mechanisms in the pathogenesis and pathophysiology of NAFLD. With this aim, we evaluated the available data in basic science and clinical studies in this field, reviewing the most recent works published on this topic.

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