These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.

High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol levels. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Since cholesterol accumulation and deposition of cholesterol crystals (CCs) triggers a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility, in preventing and reversing atherosclerosis. Here we show that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load, and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques, and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the anti-atherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Since CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.

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This article is available online at http://www.jlr.org stigmasterol (ethyl group at C24, ⌬ 22) ( 1, 2 ). In contrast to cholesterol, these sterols are exclusively derived from the diet and cannot be synthesized endogenously in mammals. A high plant sterol intake (2-2.5 g/day) leads to reduced total and LDL-cholesterol ( ‫ف‬ 12%) in the circulation ( 3, 4 ). Therefore, plant sterols are frequently applied as functional, nonprescription food additives to prevent atherosclerosis and cardiovascular diseases ( 5 ). However, administration of high-dose plant sterols results in increased serum plant sterol concentrations ( 6 ). Hard end-point studies showing an effect on the number of cardiovascular events or on mortality after long-term intake of high-dose plant sterols are lacking ( 7 ), as are insights into the underlying molecular mechanisms ( 8 ). Because adverse events upon plant sterol administration in animal studies are increasingly being reported to cause adverse events ( 9 ), it is a current topic of debate ( 10 ).In contrast to peripheral tissues, all cholesterol within the central nervous system is synthesized in situ because circulating cholesterol is not able to cross the blood-brain barrier (BBB) ( 11,12 ). Recently, we reported that circulating plant sterols, in contrast to cholesterol, can enter the brains of ATP binding cassette g5 (Abcg5)-defi cient mice, a model for phytosterolemia ( 13 ). ABCG5 and ABCG8 act as functional heterodimer transporters at the apical membranes of enterocytes and hepatocytes, where they excrete plant sterols into the intestinal lumen and bile, Abstract Plant sterols such as sitosterol and campesterol are frequently administered as cholesterol-lowering supplements in food. Recently, it has been shown in mice that, in contrast to the structurally related cholesterol, circulating plant sterols can enter the brain. We questioned whether the accumulation of plant sterols in murine brain is reversible. After being fed a plant sterol ester-enriched diet for 6 weeks, C57BL/6NCrl mice displayed signifi cantly increased concentrations of plant sterols in serum, liver, and brain by 2-to 3-fold. Blocking intestinal sterol uptake for the next 6 months while feeding the mice with a plant stanol ester -enriched diet resulted in strongly decreased plant sterol levels in serum and liver, without affecting brain plant sterol levels. Relative to plasma concentrations, brain levels of campesterol were higher than sitosterol, suggesting that campesterol traverses the blood-brain barrier more effi ciently. In vitro experiments with brain endothelial cell cultures showed that campesterol crossed the blood-brain barrier more effi ciently than sitosterol. We conclude that, over a 6-month period, plant sterol accumulation in murine brain is virtually irreversible. Plant sterols differ structurally from cholesterol by an additional methyl or ethyl group at C24 and/or a double bond at C22 ( ⌬ 22). The most prevalent plant sterols are campesterol (methyl group at C24), sitosterol (ethyl group at C24)...