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BASIC—LIVER, PANCREAS, AND BILIARY TRACT Role of Scavenger Receptor A and CD36 in Diet-Induced Nonalcoholic Steatohepatitis in Hyperlipidemic Mice
Veerle Bieghs,K. Wouters,Patrick P. J. van Gorp,M. Gijbels,Menno P. J. De Winther,Christoph J. Binder,Dieter Lütjohann,Maria Febbraio,Kathryn J. Moore,Marc van Bilsen,Marten H. Hofker,Ronit Shiri-Sverdlov +11 more
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TLDR
In this article, the authors proposed a mechanism by which Kupffer cells (KCs) take up modified cholesterol-rich lipoproteins via scavenger receptors (SRs).Abstract:
BACKGROUND & AIMS
Nonalcoholic steatohepatitis (NASH) is a disorder that consists of steatosis and hepatic inflammation. It is not known why only some people with steatosis develop NASH. Recently, we identified dietary cholesterol as a factor that directly leads to hepatic inflammation and hepatic foam cell formation. We propose a mechanism by which Kupffer cells (KCs) take up modified cholesterol-rich lipoproteins via scavenger receptors (SRs). KCs thereby accumulate cholesterol, become activated, and may then trigger an inflammatory reaction. Scavenging of modified lipoproteins mainly depends on CD36 and macrophage scavenger receptor 1.
METHODS
To evaluate the involvement of SR-mediated uptake of modified lipoproteins by KCs in the development of diet-induced NASH, female low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice were lethally irradiated and transplanted with bone marrow from Msr1(+/+)/Cd36(+/+)or Msr1(-/-)/Cd36(-/-) mice and fed a Western diet.
RESULTS
Macrophage and neutrophil infiltration revealed that hepatic inflammation was substantially reduced by approximately 30% in Msr1(-/-)/Cd36(-/-)-transplanted mice compared with control mice. Consistent with this, the expression levels of well-known inflammatory mediators were reduced. Apoptotis and fibrosis were less pronounced in Msr1(-/-)/Cd36(-/-)-transplanted mice, in addition to the protective phenotype of natural antibodies against oxidized low-density lipoprotein in the plasma. Surprisingly, the effect on hepatic inflammation was independent of foam cell formation.
CONCLUSIONS
Targeted inactivation of SR pathways reduces the hepatic inflammation and tissue destruction associated with NASH, independent of hepatic foam cell formation.read more
Citations
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The interaction of hepatic lipid and glucose metabolism in liver diseases
Lars P. Bechmann,Rebekka A. Hannivoort,Guido Gerken,Goekhan S. Hotamisligil,Michael Trauner,Ali Canbay +5 more
TL;DR: Novel findings related to nuclear receptor signaling in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of non-alcoholic fatty liver disease, liver regeneration, and cancer are focused on.
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The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Konstantin Kazankov,Simon Mark Dahl Jørgensen,Karen Louise Thomsen,Holger Jon Møller,Hendrik Vilstrup,Jacob George,Detlef Schuppan,Detlef Schuppan,Henning Grønbæk +8 more
TL;DR: Experimental and clinical data support a central role for macrophages in the development and progression of nonalcoholic fatty liver disease (NAFLD) and non alcoholic steatohepatitis (NASH) and studies investigating drugs that target macrophage recruitment to the liver, Macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH are reviewed.
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Animal models of nonalcoholic fatty liver disease
Lionel Hebbard,Jacob George +1 more
TL;DR: This Review discusses the prevalent dietary and inflammation-based genetic animal models described in recent years that have been undertaken using animals to model human steatosis and NAFLD to NASH disease progression.
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The Role of Cholesterol in the Pathogenesis of NASH
TL;DR: This review examines the effects of excess FC in hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSCs), and the subcellular mechanisms by which excess FC can induce cellular toxicity or proinflammatory and profibrotic effects in these cells.
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Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis.
TL;DR: This review focuses on cellular mechanisms of cholesterol toxicity involved in liver injury and on alterations in cholesterol homeostasis promoting hepatic cholesterol overload in NASH, and the therapeutic implications and opportunities for normalizing cellular cholesterolHomeostasis in patients.
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