Tags

Type your tag names separated by a space and hit enter

Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice.
Int J Mol Sci. 2019 Sep 01; 20(17)IJ

Abstract

Cholesterol and bile acid (BA) homeostasis plays a central role in systemic metabolism. Accumulating evidence suggests a key regulatory function of the circadian clock, our biological timer, in lipid metabolism, particularly cholesterol and bile acid flux. Previously, we showed that Nobiletin (NOB), a natural compound targeting the ROR (Retinoic acid receptor-related orphan receptor) nuclear receptors in the circadian oscillator, strongly protects lipid homeostasis, including normal serum cholesterol levels in high-fat (HF) fed mice at both young and old ages. In this study, we further examined the role of NOB in cholesterol metabolism in HF-fed aged mice, and found that NOB lowered the serum LDL/VLDL cholesterol levels and consequently the LDL/HDL ratio. BA levels in the serum were markedly reduced in the HF.NOB group, and examination of additional hepatic markers further indicate a protective role of NOB in the liver. At the molecular level, whereas HF feeding downregulated hepatic expression of several ROR target genes involved in bile acid synthesis, NOB treatment (HF.NOB) was able to rescue it. In accordance, fecal BA excretion was enhanced by NOB, and microbial 16S sequencing revealed alteration of several taxa known to be involved in secondary BA production in the gut. Together, these results demonstrate concerted effects of the clock-modulating compound NOB in cholesterol and BA metabolism, suggesting pharmacological manipulation of the clock as a novel therapeutic strategy against metabolic disorders and age-related decline.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA.Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO 80045, USA.Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO 80045, USA.Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA.Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA. Zheng.chen.1@uth.tmc.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31480535

Citation

Nohara, Kazunari, et al. "Coordinate Regulation of Cholesterol and Bile Acid Metabolism By the Clock Modifier Nobiletin in Metabolically Challenged Old Mice." International Journal of Molecular Sciences, vol. 20, no. 17, 2019.
Nohara K, Nemkov T, D'Alessandro A, et al. Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice. Int J Mol Sci. 2019;20(17).
Nohara, K., Nemkov, T., D'Alessandro, A., Yoo, S. H., & Chen, Z. (2019). Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice. International Journal of Molecular Sciences, 20(17). https://doi.org/10.3390/ijms20174281
Nohara K, et al. Coordinate Regulation of Cholesterol and Bile Acid Metabolism By the Clock Modifier Nobiletin in Metabolically Challenged Old Mice. Int J Mol Sci. 2019 Sep 1;20(17) PubMed PMID: 31480535.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coordinate Regulation of Cholesterol and Bile Acid Metabolism by the Clock Modifier Nobiletin in Metabolically Challenged Old Mice. AU - Nohara,Kazunari, AU - Nemkov,Travis, AU - D'Alessandro,Angelo, AU - Yoo,Seung-Hee, AU - Chen,Zheng, Y1 - 2019/09/01/ PY - 2019/08/03/received PY - 2019/08/28/revised PY - 2019/08/30/accepted PY - 2019/9/5/entrez PY - 2019/9/5/pubmed PY - 2020/2/15/medline KW - Nobiletin KW - aging KW - cholesterol and bile acid homeostasis KW - circadian clock modifier KW - gene expression KW - gut microbiota KW - high-fat feeding KW - liver JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 17 N2 - Cholesterol and bile acid (BA) homeostasis plays a central role in systemic metabolism. Accumulating evidence suggests a key regulatory function of the circadian clock, our biological timer, in lipid metabolism, particularly cholesterol and bile acid flux. Previously, we showed that Nobiletin (NOB), a natural compound targeting the ROR (Retinoic acid receptor-related orphan receptor) nuclear receptors in the circadian oscillator, strongly protects lipid homeostasis, including normal serum cholesterol levels in high-fat (HF) fed mice at both young and old ages. In this study, we further examined the role of NOB in cholesterol metabolism in HF-fed aged mice, and found that NOB lowered the serum LDL/VLDL cholesterol levels and consequently the LDL/HDL ratio. BA levels in the serum were markedly reduced in the HF.NOB group, and examination of additional hepatic markers further indicate a protective role of NOB in the liver. At the molecular level, whereas HF feeding downregulated hepatic expression of several ROR target genes involved in bile acid synthesis, NOB treatment (HF.NOB) was able to rescue it. In accordance, fecal BA excretion was enhanced by NOB, and microbial 16S sequencing revealed alteration of several taxa known to be involved in secondary BA production in the gut. Together, these results demonstrate concerted effects of the clock-modulating compound NOB in cholesterol and BA metabolism, suggesting pharmacological manipulation of the clock as a novel therapeutic strategy against metabolic disorders and age-related decline. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31480535/Coordinate_Regulation_of_Cholesterol_and_Bile_Acid_Metabolism_by_the_Clock_Modifier_Nobiletin_in_Metabolically_Challenged_Old_Mice_ L2 - https://www.mdpi.com/resolver?pii=ijms20174281 DB - PRIME DP - Unbound Medicine ER -