Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway

Feldstein, Ariel E.; Werneburg, Nathan W.; Canbay, Ali; Guicciardi, Maria Eugenia; Bronk, Steven F.; Rydzewski, Robert M.; Burgart, Laurence J.; Gores, Gregory J.

doi:10.1002/hep.20283

Cited by 732 publications

(317 citation statements)

References 31 publications

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“…Adipose tissue, hepatocytes, and Kupffer cells are important sources of TNF production. 40,41 A number of studies have demonstrated that free fatty acids, which blood levels are increased in NAFLD patients, induce TNF expression in hepatocytes 42 and adipocytes. 43 .…”

Section: Discussionmentioning

confidence: 99%

Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice

et al. 2006

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Section: Discussionmentioning

confidence: 99%

Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice

et al. 2006

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“…Elevated circulating FFA is an established risk factor for NAFLD (Unger & Orci 2002, Feldstein et al 2004. Serum FFA levels in HFD mice were significantly higher than those in STD mice at 8 weeks and were further increased at 20 weeks.…”

Section: Effect Of Glucose Fluctuation On Body Weight Metabolic Paramentioning

confidence: 99%

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Yin¹,

Zheng²,

Pan³

et al. 2015

Journal of Molecular Endocrinology

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Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 mmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.

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“…We first verified the time course of lipid accumulation in rat hepatoma FaO cells exposed to a FFA mixture (oleate/ palmitate 2:1 molar ratio), according to the model of 'cellular steatosis' described in human hepatoma HepG2 cells (Feldstein et al 2004) and in primary rat hepatocytes (Feldstein et al 2004, Grasselli et al 2011. FFA exposure induced a rapid time-dependent increase in lipid accumulation, evaluated by densitometric analysis of ORO staining, reaching a plateau at 3-6 h (about threefold with respect to controls; P%0 .…”

Section: Effects Of Exogenous Ffa-induced Lipid Accumulation In Fao Cmentioning

confidence: 99%

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

Grasselli

Voci

Canesi

et al. 2011

Journal of Endocrinology

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Iodothyronines influence lipid metabolism and energy homeostasis. Previous studies demonstrated that 3,5-L-diiodothyronine (T 2 ), as well as 3,3 0 ,5-L-triiodothyronine (T 3 ), was able to both prevent and reverse hepatic steatosis in rats fed a high-fat diet, and this effect depends on a direct action of iodothyronines on the hepatocyte. However, the involvement of thyroid hormone receptors (TRs) in mediating the lipid-lowering effect of iodothyronines was not elucidated. In this study, we investigated the ability of T 2 and T 3 to reduce the lipid overloading using the rat hepatoma FaO cells defective for functional TRs. The absence of constitutive mRNA expression of both TRa1 and TRb1 in FaO cells was verified by RT-qPCR. To mimic the fatty liver condition, FaO cells were treated with a fatty acid mixture and then exposed to pharmacological doses of T 2 or T 3 for 24 h. Lipid accumulation, mRNA expression of the peroxisome proliferator-activated receptors (PPAR-a, -g, -d) the acyl-CoA oxidase (AOX), and the stearoyl CoA desaturase (SCD1), as well as fuel-stimulated O 2 consumption in intact cells, were evaluated. Lipid accumulation was associated with an increase in triacylglycerol content, PPARg mRNA expression, and a decrease in PPARd and SCD1 mRNA expression. The addition of T 2 or T 3 to lipid-overloaded cells resulted in i) reduction in lipid content; ii) downregulation of PPARa, PPARg, and AOX expression; iii) increase in PPARd expression; and iv) stimulation of mitochondrial uncoupling. These data demonstrate, for the first time, that in the hepatocyte, the lipid-lowering actions of both T 2 and T 3 are not mediated by TRs.

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Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway

Cited by 732 publications

References 31 publications

Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice

Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells

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