The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice.

Gastroenterology. 2013 Jan;144(1):167-178.

Bieghs V, Hendrikx T, van Gorp PJ, Verheyen F, Guichot YD, Walenbergh SM, Jeurissen ML, Gijbels M, Rensen SS, Bast A, Plat J, Kalhan SC, Koek GH, Leitersdorf E, Hofker MH, Lütjohann D, Shiri-Sverdlov R.

Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands.

 

ABSTRACT

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis in combination with inflammation. While steatosis itself is considered benign and reversible, the presence of inflammation can lead to further liver damage. We recently demonstrated a clear association between hepatic inflammation and lysosomal cholesterol accumulation inside Kupffer cells (KCs). 27-hydroxycholesterol (27HC), a derivative of cholesterol formed by CYP27A1, has been shown in vitro to mobilize cholesterol from the lysosomes to the cytoplasm. Here, we hypothesized that 27HC can redirect the intracellular cholesterol distribution in vivo, thereby influencing hepatic inflammation.

METHODS: To investigate the role of CYP27A1 in NASH, irradiated Ldlr-/- mice were transplanted (tp) with Cyp27a1-/- and wild-type (Wt) bone marrow. After 9 weeks recovery, mice were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 3 months. To examine whether exogenous 27HC influences intracellular cholesterol distribution and hepatic inflammation, 27HC was administered subcutaneously to Ldlr-/- mice that received regular chow or an HFC diet for 3 weeks.

RESULTS: Electron microscopy analysis of KCs revealed more lysosomal cholesterol accumulation in Cyp27a1-/--tp mice than in Wt-tp mice after HFC feeding. Liver histology and gene expression showed increased inflammation and liver damage in HFC-fed Cyp27a1-/--tp mice. In line with these data, administration of 27HC to Ldlr-/- mice on an HFC diet led to reduced lysosomal cholesterol accumulation and hepatic inflammation.

CONCLUSIONS: These data support a causal role for lysosomal cholesterol accumulation in hepatic inflammation and underline the potential of using 27HC as a treatment for NASH.

KEYWORDS: Hepatic inflammation; Cholesterol; CYP27A1; Kupffer cells

Ronit Shiri-Sverdlov-1

Ronit Shiri-Sverdlov-2

A. Normal conditions: circulating non-modified lipids (LDL), are taken up by Kupffer cells and initially directed to lysosomes. After hydrolysis, cholesterol is transferred into the cytoplasm via Niemann-Pick type C (NPC) proteins. Conversion of cholesterol to 27-Hydroxycholesterol (27HC) enhances the translocation of cholesterol from the lysosomes to the cytoplasm. Under these conditions, inflammation is prevented.

B. NASH: circulating oxidized lipids (oxLDL) are taken up by Kupffer cells via scavenger receptors (CD36 and MSR1) and directed to lysosomes. However, unlike non-modified LDL, oxLDL is not transferred into the cytoplasm, but rather accumulates in lysosomes. Reduced levels of cholesterol in the cytoplasm lead to decreased levels of 27HC, thereby further increasing the accumulation of cholesterol in lysosomes. Under these conditions, inflammation is present.

 

This research was patented with title: “Method for treating fatty liver diseases, in particular non-alcoholic steatohepatitis”. Patent number: WO 2012019930 A1

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