Hepatic Free Fatty Acids in Alcoholic Liver Disease and Morbid Obesity

Mavrelis, Peter G.; Ammon, Helmut V.; Gleysteen, J.J.; Komorowski, Richard; Charaf, Ursula K.

doi:10.1002/hep.1840030215

Cited by 88 publications

(44 citation statements)

References 24 publications

(29 reference statements)

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“…The magnification is ×400. [28] . Furthermore, FFAs not only promote hepatic lipotoxicity via a lysosomal pathway [29] but are also the most important source of reactive oxygen species (ROS) [30,31] .…”

Section: Discussionmentioning

confidence: 99%

Protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats

et al. 2012

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Aim: To study the protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats. Methods: Male Sprague-Dawley rats were given a high-fat diet for 10 weeks. The rats were administered tiopronin (20 mg/kg) or a positive control drug ursodeoxycholic acid (UDCA, 15 mg/kg) via gavage daily from week 5 to week 10. After the rats were sacrificed, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), and liver homogenate FFA, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial analysis kits. The expression levels of CYP2E1 mRNA and protein were determined using RT-PCR and immunoblot assays, respectively. Results: Tiopronin significantly lowered both the serum ALT and AST levels, while only the serum ALT level was lowered by UDCA. Tiopronin significantly decreased the serum and liver levels of TG, TC and FFA as well as the serum LDL-C level, and increased the serum HDL-C level, while UDCA decreased the serum and liver TC levels as well as the serum LDL-C level, but did not change the serum levels of TG, FFA and HDL-C. Tiopronin apparently ameliorated the hepatocyte degeneration and the infiltration of inflammatory cells in the livers, but UDCA did not affect the pathological features of the livers. Both tiopronin and UDCA ameliorated the mitochondrial abnormality in the livers. The benefits of tiopronin were associated with increased SOD and GSH-Px activities, and with decreased MDA activity and CYP2E1 expression in the livers. Conclusion: Tiopronin exerts protective effects against non-alcoholic steatohepatitis in rats, which may be associated with its antioxidant properties and regulation of lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

Protective effects of tiopronin against high fat diet-induced non-alcoholic steatohepatitis in rats

et al. 2012

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“…Patients with NAFLD show increased lipolysis and augmented delivery of FFA to the liver [113,118], the concentration of which are associated with more severe liver disease [119]. Elevated FFA in the liver [120] act as ligands for the transcription factor PPARa, which upregulates the oxidation of FFA inside the mitochondria, microsomes, and peroxisomes [121]. The FFA oxidation products (lipid peroxides and superoxide and hydrogen peroxide radicals) can generate oxidative stress and subsequent lipid peroxidation.…”

Section: Lipid Peroxidationmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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“…31 FFAs are the likely source of oxidative stress within the liver in these patients. Elevated FFAs within the liver 33 act as ligands for the transcription factor peroxisome proliferator-activated receptor (PPAR)-α, which upregulates the oxidation of FFAs in mitochondria. 34 It is believed that the inability of mitochondria to adapt to chronic high levels of FFA supply/flux leads to its ultimate demise, followed by cell injury and death.…”

Section: Lipotoxicitymentioning

confidence: 99%