Role of Scavenger Receptor A and CD36 in Diet-Induced Nonalcoholic Steatohepatitis in Hyperlipidemic Mice

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 fibro-sis 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.

A novel murine model for non-alcoholic steatohepatitis developed by combination of a high-fat diet and oxidized low-density lipoprotein

“…19,20 Kupffer cells, the main liver site for oxLDL uptake, reportedly lead to hepatic inflammation through the process of oxLDL uptake. 11 As expected, HFD þ oxLDL animals showed increased accumulation of inflammatory cells and severe hepatocellular injury, as well as high expression levels of both the TNF-a and IL-6 genes (Figures 1b and c, 2a and 4a-f, and Table 4). Additionally, inflammatory infiltration and foamy macrophages were also observed in the livers of RD þ oxLDL mice, which were accompanied by enhanced gene expression of IL-6 but not TNF-a (Figures 2a and c, and 4a-f, and Table 4).…”

“…7 The current view from experimental studies on the pathogenesis of NASH is also consistent with the importance of steatosis in the development of NASH. 11,34 Thus, we first established a dietary model for hepatic steatosis by feeding wild-type mice an HFD for 23 weeks (Figures 1a, and 2a and c; Tables 3 and 4). Biochemical analyses verified alterations in lipid metabolism in these mice (Table 4).…”

“…This process represents a key step in the development of NASH. Although risk factors such as oxidative stress, mitochondrial injury, innate immunity, and proinflammatory cytokines have been implicated in the development of hepatic inflammation, 11,12 the actual trigger for tissue inflammation and hepatocyte degeneration remains uncertain. Currently, increasing emphasis has been placed on oxidization of lipids and proteins as core events of inflammation associated with NASH.…”

Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis

“…However, they postulated that this cholesterol was derived from uptake of modified circulating lipoproteins by scavenger receptors on the Kupffer cells ( 24,25 ). While this process may also be occurring, our results suggest that processing of remnant lipid droplets from dead steatotic hepatocytes represents an important mechanism by which macrophages acquire cholesterol.…”

“…In a series of excellent recent papers, Dutch investigators identifi ed foamy Kupffer cells in the liver of LDL receptor-defi cient mice fed a high-fat high-cholesterol diet (22)(23)(24)(25)(26). However, they postulated that this cholesterol was derived from uptake of modified circulating lipoproteins by scavenger receptors on the Kupffer cells ( 24,25 ).…”