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.
Highlights
Non-alcoholic steatohepatitis (NASH) is increasingly recognized as a major health burden in developed countries, with a prevalence of 2–3% in the general population and up to 37% of the severely obese population of Western countries [1]
Inflammation is reduced in Cd362/2-tp and Msr12/2-tp mice compared to Wt-tp mice
To determine whether both Cd36 and macrophage scavenger receptor 1 (Msr1) are independently involved in diet-induced hepatic inflammation, Ldlr2/2 mice were transplanted with Cd362/2 or Msr12/2 bone marrow and fed a HFC diet for 3 months
Summary
Non-alcoholic steatohepatitis (NASH) is increasingly recognized as a major health burden in developed countries, with a prevalence of 2–3% in the general population and up to 37% of the severely obese population of Western countries [1] It is characterized by hepatic lipid accumulation (steatosis) combined with inflammation. The individual contributions of these receptors to the onset of inflammation and the intracellular mechanisms by which they contribute to inflammation have not yet been established Based on their different functions in inflammatory signal transduction, we hypothesized that CD36 and MSR1 contribute independently to the onset of hepatic inflammation, by affecting intracellular cholesterol distribution inside KCs. Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation, which can further progress into fibrosis and cirrhosis. We hypothesize that CD36 and MSR1 contribute independently to the onset of inflammation in NASH, by affecting intracellular cholesterol distribution inside Kupffer cells (KCs)
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