Dietary Supplementation with 22‐S‐Hydroxycholesterol to Rats Reduces Body Weight Gain and the Accumulation of Liver Triacylglycerol

Abstract

This study explores the pharmacokinetics of 22-S-hydroxycholesterol (22SHC) in vivo in rats. We also carried out a metabolic study to explore whether the beneficial effects observed of 22SHC on glucose and lipid metabolism in vitro could be seen in vivo in rats. In the pharmacokinetic study, rats were given 50 mg/kg of [³H]22-S-hydroxycholesterol before absorption, distribution and excretion were monitored. In the metabolic study, the effect of 22SHC (30 mg/kg/day for 3 weeks) in rats on body weight gain [chow and high-fat diet (HFD)], serum lipids triacylglycerol (TAG) content and gene expression in liver and skeletal muscle were examined. Results showed that 22SHC was well absorbed after oral administration and distributed to most organs and mainly excreted in feces. Rats receiving 22SHC gained less body weight than their controls regardless whether the animals received chow diet or HFD. Moreover, we observed that animals receiving HFD had elevated levels of serum TAG while this was not observed for animals on HFD supplemented with 22SHC. The amount of TAG in liver was reduced after 22SHC treatment in animals receiving either chow diet or HFD. Gene expression analysis revealed that two genes (carnitine palmitoyltransferase 2 and uncoupling protein 3) involved in fatty acid oxidation and energy dissipation were increased in liver. Ucp3 expression (both protein and mRNA level) was increased in skeletal muscle, but insulin-stimulated glucose uptake and TAG content were unchanged. In conclusion, 22SHC seems to be an interesting model substance in the search of treatments for disorders involving aberrations in lipid metabolism.

The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis

“…In miR-155 −/− macrophages, this was associated with an increased profibrotic (M2) phenotype characterized by increased expression of Arg2 , a key enzyme controlling the bioavailability of hydroxyproline for collagen synthesis 27 (Fig 2, J ). We demonstrated that this increased Arg2 expression in miR-155 −/− macrophages was restored to normal by Lxrα- siRNA (Fig 2, K ; see Fig E5, A , in this article's Online Repository at www.jacionline.org) and by LXR antagonist 22(S)-hydroxycholesterol (22(S)HC) 28 (Fig 2, L ). To extend this to human cells, we investigated the regulatory interrelationship between LXRα and miR-155 in the expression of ARG2 in human macrophages.…”

LXR antagonists induce ABCD2 expression

“…The details of this animal study have been previously published [34]. In summary, male Wistar rats were fed ad libitum a regular maintenance diet (Special Diets Services, Witham, Essex, UK) for 5 days after arrival to our animal facilities.…”

“…Liver was collected from each rat and stored at −70°C. The tissues were homogenized and total RNA were isolated and reversely transcribed as previously described [34]. Real time qPCR was performed using an ABI PRISM® 7000 Detection System.…”

“…The expression levels of carnitine palmitoyl transferase 2 and uncoupling protein 3 have been shown to be induced in liver of rats fed a normal or high fat diet enriched in 22S-HC (30 mg/kg/day for 3 weeks) [34]. In order to study whether 22S-HC could induce hepatic expression of Abcd2, Abcd3 or Ctnnb1 in vivo, cDNA samples from these rats were analyzed by RT-qPCR.…”

(2S,3S)-2,6-Dimethylheptane-1,3-diol, the oxygenated side chain of 22(S)-hydroxycholestrol, and its synthetic precursor (R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2,6-dimethylheptanoyl]-1,3-oxazolidin-2-one

“…This urged us to initiate a drug-design programme, starting with a retrosynthetic analysis for the establishment of synthetic routes to the pharmacophores in the different OHCs reported to affect the various diseases referred to above. Our first focus aimed at a stereoselective synthesis of the oxygenated side chains in 22(R)-and 22(S)-hydroxycholesterol, which have agonistic and antagonistic effects on LXR, respectively Kase et al, 2012). (2S,3S)-2,6-Dimethylheptane-1,3-diol, (I), is a new chemical entity representing the oxygenated side chain in 22(S)-hydroxycholesterol, and is the starting material in a synthetic programme aimed at a new class of potential drug candidates as selective regulators of the LXR receptor and the Hh pathway.…”