Internalization of Modified Lipids by CD36 and SR-A Leads to Hepatic Inflammation and Lysosomal Cholesterol Storage in Kupffer Cells

Abstract

Background & AimsNon-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. Recently, we demonstrated that combined deletion of the two main scavenger receptors, CD36 and macrophage scavenger receptor 1 (MSR1), which are important for modified cholesterol-rich lipoprotein uptake, reduced NASH. The individual contributions of these receptors to NASH and the intracellular mechanisms by which they contribute to inflammation have not been established. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs).Methods & Results Ldlr−/− mice were transplanted with wild-type (Wt), Cd36−/− or Msr1−/− bone marrow and fed a Western diet for 3months. Cd36−/−- and Msr1−/−- transplanted (tp) mice showed a similar reduction in hepatic inflammation compared to Wt-tp mice. While the total amount of cholesterol inside KCs was similar in all groups, KCs of Cd36−/−- and Msr1−/−-tp mice showed increased cytoplasmic cholesterol accumulation, while Wt-tp mice showed increased lysosomal cholesterol accumulation.ConclusionCD36 and MSR1 contribute similarly and independently to the progression of inflammation in NASH. One possible explanation for the inflammatory response related to expression of these receptors could be abnormal cholesterol trafficking in KCs. These data provide a new basis for prevention and treatment of 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 ).…”

High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes

“…FAT/CD36 expresses in hepatocytes, endothelial cells, and Kupffer cells (7,17,27), so it would not be surprising that the increase in liver FAT/CD36 protein content could be due in part to steatosisassociated tissular enrichment in Kupffer cells. Bieghs and colleagues (6,7) demonstrated that targeted inactivation of scavenger receptors A and CD36 in Kupffer cells reduced the hepatic inflammation and tissue destruction associated with nonalcoholic steatohepatitis. In a previous work (9), we demonstrated that OZ12 rats exhibited greater hepatosteatosis histological grade, liver damage, and body weight gain than OZ6 and OZ9 rats.…”

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

“…These macrophage-derived foam cells predominantly contain enlarged lysosomes filled with cholesterol and cholesterol crystals. Additional evidence showed that increased cholesterol storage inside lysosomes of KCs is associated with hepatic inflammation in the context of NASH [71, 72]. …”