LIGHT/TNFSR14 Can Regulate Hepatic Lipase Expression by Hepatocytes Independent of T Cells and Kupffer Cells

Chellan, Bijoy; Koroleva, Ekaterina P.; Sontag, Timothy J.; Tumanov, Alexei V.; Fu, Yang–Xin; Getz, Godfrey S.; Reardon, Catherine A.

doi:10.1371/journal.pone.0054719

Cited by 10 publications

(9 citation statements)

References 49 publications

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“…Moreover, Light deficiency decreased insulin resistance in HFHCD-fed WT mice, suggesting that LIGHT could interfere with insulin sensitivity, as has been shown for other cytokines such as TNF-α [24]. LIGHT exerts important effects on circulating lipid levels by modulating hepatocyte gene expression and hepatic T lymphocytes [23,25]. However Light deficiency did not modify circulating lipid levels in WT mice.…”

Section: Discussionmentioning

confidence: 79%

Genetic inactivation of the LIGHT (TNFSF14) cytokine in mice restores glucose homeostasis and diminishes hepatic steatosis

et al. 2019

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Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) is frequently associated with type 2 diabetes mellitus. Progression of NAFLD is mediated, among other things, by activation of inflammatory pathways. In the present study, the role of the proinflammatory cytokine LIGHT (TNFSF14) was explored in NAFLD and type 2 diabetes mellitus in mice deficient for the cytokine. Methods Light-deficient (Light −/−) mice and WT controls were fed a regular chow diet (RCD) or a high-fat high-cholesterol diet (HFHCD) for 16 weeks. The expression of LIGHT and its receptors, herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR), was investigated in both dietary regimens. Glucose tolerance, insulin sensitivity, non-alcoholic fatty liver (NAFL), systemic and tissue inflammation, and metabolic gene expression were explored in Light −/− and WT mice fed an RCD and an HFHCD. The effect of Light deficiency was also evaluated in hepatic tissue and in inflammation in HFHCD-fed Irs2 +/− mice with impaired insulin signalling. Results Light deficiency did not have an effect on metabolism, in NAFL or in tissue and systemic inflammation, in RCD-fed WT mice. HVEM and LTβR were markedly increased in livers of HFHCD-fed WT mice compared with RCD-fed WT controls. In WT mice under HFHCD, Light deficiency improved glucose tolerance and insulin sensitivity. Non-alcoholic fatty liver disease activity (NAS) score, hepatic CD3 + T lymphocytes and F4/80 + macrophages were decreased in HFHCD-fed Light −/− mice compared with HFHCD-fed WT controls. Consistent with a potential role of adipose tissue in hepatic homeostasis, Light −/− mice exhibited augmented anti-inflammatory F4/80 + CD206 + adipose tissue macrophages and reduced proinflammatory F4/ 80 + CD11c + adipose tissue macrophages. Moreover, adipose tissue explants from Light −/− mice showed diminished secretion of monocyte chemoattractant protein 1 (MCP1), TNF-α and IL-17 cytokines. Circulating Light −/− leucocytes consistently displayed augmented levels of the patrolling Ly6C low monocytes, decreased Th9 T cell subset and diminished plasma TNF-α and IL-6 levels. Similarly, Light deficiency in Irs2 +/− mice, which display impaired insulin signalling, also reduced NAFL as well as systemic and adipose tissue inflammation. Analysis of hepatic gene expression in Light −/− mouse livers showed reduced levels of Zbtb16, the transcription factor essential for natural killer T (NKT) cell function, and two genes related to NAFLD and fibrosis, Klf6 and Tlr4. Conclusions/interpretation These results indicate that Light deficiency in HFHCD improves hepatic glucose tolerance, and reduces hepatic inflammation and NAFL. This is accompanied by decreased systemic inflammation and adipose tissue cytokine secretion and by changes in the expression of key genes such as Klf6 and Tlr4 involved in NAFLD. These results suggest that therapies to block LIGHT-dependent signalling might be useful to restore hepatic homeostasis and to restrain NAFLD.

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Section: Discussionmentioning

confidence: 79%

Genetic inactivation of the LIGHT (TNFSF14) cytokine in mice restores glucose homeostasis and diminishes hepatic steatosis

et al. 2019

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“…Since the activity of HL is known to be inversely correlated with the plasma HDL levels [2] the study of factors which regulate HL activity is important in understanding the regulation of HDL metabolism. Whereas the regulation of HL transcription, synthesis and secretion from the liver have been well studied [1,6–8], the physiological factors that regulate its activity in the plasma compartment are not well understood. Furthermore, while it is known that HL acts preferentially on HDL compared to VLDL and LDL [4], the reason for this specificity is unknown, since it does not require an apoprotein cofactor for its activity.…”

Section: Introductionmentioning

confidence: 99%

Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins

Yang

Subbaiah

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Hepatic lipase (HL) is an important enzyme in the clearance of triacylglycerol (TAG) from the circulation, and has been proposed to have pro-atherogenic as well as anti-atherogenic properties. It hydrolyzes both phospholipids and TAG of lipoproteins, and its activity is negatively correlated with HDL levels. Although it is known that HL acts preferentially on HDL lipids, the basis for this specificity is not known, since it does not require any specific apoprotein for activity. In this study, we tested the hypothesis that sphingomyelin (SM), whose concentration is much higher in VLDL and LDL compared to HDL, is an inhibitor of HL, and that this could explain the lipoprotein specificity of the enzyme. The results presented show that the depletion of SM from normal lipoproteins activated the HL roughly in proportion to their SM content. SM depletion stimulated the hydrolysis of both phosphatidylcholine (PC) and TAG, although the PC hydrolysis was stimulated more. In the native lipoproteins, HL showed specificity for PC species containing polyunsaturated fatty acids at sn-2 position, and produced more unsaturated lyso PC species. The enzyme also showed preferential hydrolysis of certain TAG species over others. SM depletion affected the specificity of the enzyme towards PC and TAG species modestly. These results show that SM is a physiological inhibitor of HL activity in lipoproteins and that the specificity of the enzyme towards HDL is at least partly due to its low SM content.

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“…We have studied LIGHT expressed as a transgene in T cells and shown that it substantially down regulates the expression of hepatic lipase, a plasma enzyme involved in HDL metabolism 42 . We have also shown that the expression of LIGHT primarily by hepatocytes in mice using an adenovirus also reduces hepatic lipase expression independent of T cells 43 . In the presence of LIGHT overexpressing T cells in WTD fed Ldlr−/− mice a novel large HDL-like lipoprotein, HDL1, which is almost devoid of apoA-I, but is rich in apoE appears in the plasma.…”

Section: T Cell Costimulatory/coinhibitory Moleculesmentioning

confidence: 69%

T Cells in Atherosclerosis in Ldlr-/- and Apoe-/- Mice

Getz

Reardon

2018

J Immunological Sci

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Atherosclerosis is the underlying basis for most cardiovascular diseases. It is a chronic inflammation affecting the arterial intima and is promoted by hypercholesterolemia. Cells of both the innate and adaptive immune systems contribute to this inflammation with macrophages and T cells being the most abundant immune cells in the atherosclerotic plaques. In this review, we discuss the studies that examined the role of T cells and T cell subsets in Apoe−/− and Ldlr−/− murine models of atherosclerosis. While there is a general consensus that Th1 cells are pro-atherogenic and regulatory T cells are atheroprotective, the role of other subsets is more ambiguous. In addition, the results in the two models of atherosclerosis do not always yield similar results. Additional studies in the two murine models using cell specific gene manipulations are needed.

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LIGHT/TNFSR14 Can Regulate Hepatic Lipase Expression by Hepatocytes Independent of T Cells and Kupffer Cells

Cited by 10 publications

References 49 publications

Genetic inactivation of the LIGHT (TNFSF14) cytokine in mice restores glucose homeostasis and diminishes hepatic steatosis

Genetic inactivation of the LIGHT (TNFSF14) cytokine in mice restores glucose homeostasis and diminishes hepatic steatosis

Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins

T Cells in Atherosclerosis in Ldlr-/- and Apoe-/- Mice

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