The Cholesterol Derivative 27-Hydroxycholesterol Reduces Steatohepatitis in Mice

Bieghs, Veerle; Hendrikx, Tim; Gorp, Patrick J. van; Verheyen, Fons; Guichot, Yasmin Dias; Walenbergh, Sofie M. A.; Jeurissen, Mike L. J.; Gijbels, Marion J.J.; Rensen, Sander S.; Bast, Aalt; Plat, Jogchum; Kalhan, Satish C.; Koek, Ger H.; Leitersdorf, Eran; Hofker, Marten H.; Lütjohann, Dieter; Shiri-Sverdlov, R.

doi:10.1053/j.gastro.2012.09.062

Cited by 83 publications

(101 citation statements)

References 42 publications

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“…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 ).…”

Section: Discussionmentioning

confidence: 99%

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

Ioannou

Haigh

Thorning

et al. 2013

Journal of Lipid Research

202

191

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We sought to determine whether hepatic cholesterol crystals are present in patients or mice with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH), and whether their presence or distribution correlates with the presence of NASH as compared with simple steatosis. We identifi ed, by fi lipin staining, free cholesterol within hepatocyte lipid droplets in patients with NASH and in C57BL/6J mice that developed NASH following a highfat high-cholesterol diet. Under polarized light these lipid droplets exhibited strong birefringence suggesting that some of the cholesterol was present in the form of crystals. Activated Kupffer cells aggregated around dead hepatocytes that included strongly birefringent cholesterol crystals, forming "crown-like structures" similar to those recently described in infl amed visceral adipose tissue. These

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Section: Discussionmentioning

confidence: 99%

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

Ioannou

Haigh

Thorning

et al. 2013

Journal of Lipid Research

202

191

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“…It is evident that absence of the regulator oxysterol 27HC in patients with CYP27A1 deficiency (cerebrotendinous xanthomatosis) is associated with accumulation of lipids and accelerated tendency to develop atherosclerosis (55). Administration of 27HC to hyperlipidemic mice, followed by high fat diet, could reduce hepatic inflammation in nonalcoholic fatty liver disease (56). Both nonalcoholic fatty liver disease and atherosclerosis are major disorders of lipid metabolism, often related to obesity or abnormal distribution of body fat (57,58).…”

Section: Discussionmentioning

confidence: 99%

De Novo Synthesis of Steroids and Oxysterols in Adipocytes

Daly

Campioli

et al. 2014

Journal of Biological Chemistry

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Background: Adipocytes are known to metabolize but not synthesize de novo steroids or oxysterols. Results: CYP11A1 in adipocytes is able to synthesize pregnenolone; 27-hydroxycholesterol (27HC) is a major cholesterol metabolite in adipocytes exhibiting anti-adipogenic activity. Conclusion: Adipocytes have the ability to synthesize steroids and oxysterols de novo. Significance: Formation of 27HC in adipocytes may prevent the enlargement of adipose tissue compartment.

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“…The administration of 27-OHC to LDL receptor KO mice has been shown to reduce the accumulation of lysosomal cholesterol and hepatic inflammation in the liver (Bieghs et al 2013). If reduced 27-OHC concentrations are found in the circulation of patients with fatty liver, enhancement of the activity of CYP27A1 might then be a viable therapeutic option.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo

Vögeli¹,

Jung²,

Dick³

et al. 2013

Journal of Endocrinology

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The intracellular availability of glucocorticoids is regulated by the enzymes 11b-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11b-hydroxysteroid dehydrogenase 2 (HSD11B2). The activity of HSD11B1 is measured in the urine based on the (tetrahydrocortisolC5a-tetrahydrocortisol)/tetrahydrocortisone ((THFC5a-THF)/THE) ratio in humans and the (tetrahydrocorticosteroneC5a-tetrahydrocorticosterone)/tetrahydrodehydrocorticosterone ((THBC5a-THB)/THA) ratio in mice. The cortisol/cortisone (F/E) ratio in humans and the corticosterone/11-dehydrocorticosterone (B/A) ratio in mice are markers of the activity of HSD11B2. In vitro agonist treatment of liver X receptor (LXR) downregulates the activity of HSD11B1. Sterol 27-hydroxylase (CYP27A1) catalyses the first step in the alternative pathway of bile acid synthesis by hydroxylating cholesterol to 27-hydroxycholesterol (27-OHC). Since 27-OHC is a natural ligand for LXR, we hypothesised that CYP27A1 deficiency may up-regulate the activity of HSD11B1. In a patient with cerebrotendinous xanthomatosis carrying a loss-of-function mutation in CYP27A1, the plasma concentrations of 27-OHC were dramatically reduced (3.8 vs 90-140 ng/ml in healthy controls) and the urinary ratios of (THFC5a-THF)/THE and F/E were increased, demonstrating enhanced HSD11B1 and diminished HSD11B2 activities. Similarly, in Cyp27a1 knockout (KO) mice, the plasma concentrations of 27-OHC were undetectable (!1 vs 25-120 ng/ml in Cyp27a1 WT mice). The urinary ratio of (THBC5a-THB)/THA was fourfold and that of B/A was twofold higher in KO mice than in their WT littermates. The (THBC5a-THB)/THA ratio was also significantly increased in the plasma, liver and kidney of KO mice. In the liver of these mice, the increase in the concentrations of active glucocorticoids was due to increased liver weight as a consequence of Cyp27a1 deficiency. In vitro, 27-OHC acts as an inhibitor of the activity of HSD11B1. Our studies suggest that the expression of CYP27A1 modulates the concentrations of active glucocorticoids in both humans and mice and in vitro. Journal of EndocrinologyResearch I VÖ GELI and others CYP27A1 and glucocorticoid metabolism in vivo

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The Cholesterol Derivative 27-Hydroxycholesterol Reduces Steatohepatitis in Mice

Abstract: Accumulation of cholesterol in lysosomes of Kupfer cells promotes hepatic inflammation in mice. The cholesterol derivative 27HC reduces accumulation of cholesterol in lysosomes and might be used to treat non-alcoholic steatohepatitis.

Cited by 83 publications

References 42 publications

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

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

De Novo Synthesis of Steroids and Oxysterols in Adipocytes

Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo

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