Food-derived peroxidized fatty acids may trigger hepatic inflammation: A novel hypothesis to explain steatohepatitis

Böhm, Therese; Berger, Heidi; Nejabat, Marzieh; Riegler, Teresa; Kellner, Florian; Kuttke, Mario; Sagmeister, Sandra; Bazanella, Monika; Stolze, Klaus; Daryabeigi, Anahita; Bintner, Nora; Murkovic, Michaël; Wagner, Karl‐Heinz; Schulte‐Hermann, Rolf; Rohr-Udilova, Nataliya; Huber, Wolfgang; Grasl‐Kraupp, Bettina

doi:10.1016/j.jhep.2013.04.025

Cited by 45 publications

(47 citation statements)

References 36 publications

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“…Since the involvement of free fatty acids, products of phospholipase A2 activity, in the triggering of MPT was shown [40], lipoperoxidation products and superoxide anion are thought to play an important role in this event in the environment of enhanced oxidative stress. TFP is also known to inhibit phospholipase A2 activity which may explain more effective prevention of tBHP-induced cytotoxicity in hepatocytes, in comparison with cyclosporine A. Bohm et al showed that feeding rats corn oil containing peroxidized fatty acids may trigger the development of hepatic inflammation [41]. Thus, lipoperoxidation participates considerably in the pathogenesis of NAFLD and mediates progression from simple steatosis to advanced forms of NAFLD [42] with further increasing of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

The Effect oftert-Butyl Hydroperoxide-Induced Oxidative Stress on Lean and Steatotic Rat HepatocytesIn Vitro

Kučera

Endlicher

Roušar

et al. 2014

Oxidative Medicine and Cellular Longevity

113

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Oxidative stress and mitochondrial dysfunction play an important role in the pathogenesis of nonalcoholic fatty liver disease and toxic liver injury. The present study was designed to evaluate the effect of exogenous inducer of oxidative stress (tert-butyl hydroperoxide, tBHP) on nonfatty and steatotic hepatocytes isolated from the liver of rats fed by standard and high-fat diet, respectively. In control steatotic hepatocytes, we found higher generation of ROS, increased lipoperoxidation, an altered redox state of glutathione, and decreased ADP-stimulated respiration using NADH-linked substrates, as compared to intact lean hepatocytes. Fatty hepatocytes exposed to tBHP exert more severe damage, lower reduced glutathione to total glutathione ratio, and higher formation of ROS and production of malondialdehyde and are more susceptible to tBHP-induced decrease in mitochondrial membrane potential. Respiratory control ratio of complex I was significantly reduced by tBHP in both lean and steatotic hepatocytes, but reduction in NADH-dependent state 3 respiration was more severe in fatty cells. In summary, our results collectively indicate that steatotic rat hepatocytes occur under conditions of enhanced oxidative stress and are more sensitive to the exogenous source of oxidative injury. This confirms the hypothesis of steatosis being the first hit sensitizing hepatocytes to further damage.

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Section: Discussionmentioning

confidence: 99%

The Effect oftert-Butyl Hydroperoxide-Induced Oxidative Stress on Lean and Steatotic Rat HepatocytesIn Vitro

Kučera

Endlicher

Roušar

et al. 2014

Oxidative Medicine and Cellular Longevity

113

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“…Although the cellular mechanisms by which OXLAMs cause liver injury are only partially known, they involve Kupffer cell activation. In fact, animal studies have demonstrated that peroxidized forms of LA cause an increase of TNF-α, a strong proinflammatory signal, in Kupffer cells [52]. In vitro studies have also demonstrated that LA promotes endoplasmic reticulum stress and liver cell apoptosis through the modulation of cytochrome C expression [53].…”

Section: La-oxidized Metabolites As Biomarkers Of Disease Severity Inmentioning

confidence: 99%

Oxidized metabolites of linoleic acid as biomarkers of liver injury in nonalcoholic steatohepatitis

Santoro

Caprio

Feldstein

2013

Clinical Lipidology

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The rising prevalence of obesity in the last few decades has been accompanied by an increase in nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of liver pathology from isolated hepatic steatosis to steatohepatitis and advanced fibrosis. Dietary habits characterized by consumption of high-caloric, lipid-rich diets play a major role in the development of NAFLD. Recent studies have uncovered the importance of certain components of the diet. In this review, we will focus on the growing evidence for a central role of n-6 polyunsaturated fatty acids. We will discuss novel findings linking oxidative stress and increased production of reactive oxygen species in the liver to oxidation of n-6 polyunsaturated fatty acids and production of specific lipid oxidation metabolites. In particular, we will highlight the potential role of these metabolites as noninvasive markers to diagnose and monitor the extent of liver damage in patients with NAFLD.

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“…First, oxidative stress-mediated JNK activation induces lipid accumulation through the inhibition of insulin signaling [25][26][27] . Second, an increase in lipid peroxides causes inflammation and fibrosis via activating liver macrophages and hepatic stellate cells 28,29 . Third, the antioxidant carotenoids, astaxanthin and β-cryptoxanthin, not only decrease CL diet-induced lipid peroxidation, but also alleviate steatohepatitis, including hepatic steatosis, inflammation, and fibrosis 21,22 .…”

Section: Discussionmentioning

confidence: 99%

Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice

Nishikawa

Nagata

Shimakami

et al. 2020

Sci Rep

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Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia. Nonalcoholic fatty liver disease (NAFLD), one of the most common liver diseases worldwide 1 , is strongly associated with insulin resistance and features of metabolic syndrome such as obesity, hyperlipidemia, and type 2 diabetes 1,2. NAFLD ranges from simple steatosis to more advanced nonalcoholic steatohepatitis (NASH) characterized by steatosis in combination with inflammation and fibrosis 3,4. Besides insulin resistance, increased inflammatory cytokines, reactive oxygen species (ROS), and subsequent lipid peroxidation are thought to drive the progression of NASH, leading to liver cirrhosis and hepatocellular carcinoma 3,5. Thus, in addition to conventional approaches based on of diet-and exercise-related adjunct therapies, an effective therapeutic approach is urgently needed for NASH. Besides metabolic syndrome-related conditions, hyperuricemia, characterized by high serum uric acid (UA) levels, has also been linked to NAFLD. Several epidemiological studies have demonstrated that patients with NAFLD have significantly higher serum UA levels relative to controls, and elevated serum UA levels are an independent risk factor for NAFLD 6-8. Notably, UA itself has been reported to promote de novo lipogenesis and induce insulin resistance, both in vivo and in vitro, through increased NADPH oxidase (NOX)-mediated ROS

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Food-derived peroxidized fatty acids may trigger hepatic inflammation: A novel hypothesis to explain steatohepatitis

Cited by 45 publications

References 36 publications

The Effect oftert-Butyl Hydroperoxide-Induced Oxidative Stress on Lean and Steatotic Rat HepatocytesIn Vitro

The Effect oftert-Butyl Hydroperoxide-Induced Oxidative Stress on Lean and Steatotic Rat HepatocytesIn Vitro

Oxidized metabolites of linoleic acid as biomarkers of liver injury in nonalcoholic steatohepatitis

Xanthine oxidase inhibition attenuates insulin resistance and diet-induced steatohepatitis in mice

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