Anders Naar, PhD

Gene regulatory and microRNA circuits governing cholesterol/lipid metabolism

Our research is focused on elucidating molecular mechanisms of gene regulation, with emphasis on disease-associated pathways contributing to cholesterol/lipid disorders.

  1. Cholesterol/lipid regulation by the SREBP transcription factors. Part of our effort is centered on understanding how transcriptional regulators activate or repress target gene expression. One area of interest concerns the regulatory circuits governing cholesterol/lipid homeostasis. Aberrant regulation of cholesterol and other lipids contributes to major human diseases such as type II diabetes, the metabolic syndrome, atherosclerosis, Alzheimer’s disease, and many types of cancers, thus highlighting the importance of understanding how cholesterol/lipid homeostasis is controlled. Our work on the sterol regulatory element-binding protein (SREBP) transcription factor family, master regulators of cholesterol/lipid biosynthesis and metabolism, has provided key mechanistic insights into gene regulatory pathways guiding metabolic homeostasis. For example, we have found that a specific subunit (ARC105/MED15) of the Mediator co-activator, a large multi-protein assembly, plays a critical role in mediating SREBP-dependent activation of genes controlling cholesterol/lipid homeostasis (Yang et al. Nature 2006). Our studies have also revealed a critical role for orthologs of the NAD+-dependent deacetylase SIRT1 in negative regulation of SREBPs during fasting from C. elegans to mammals, with important implications for human cholesterol/lipid disorders (Walker et al. Genes Dev 2010). Recent studies in the lab have also uncovered a novel SREBP-regulatory feedback circuit linking production of the key membrane phospholipid phosphatidylcholine to SREBP-dependent control of hepatic lipogenesis. (Walker et al. Cell 2011). These insights may yield novel treatment modalities for nonalcoholic fatty liver diseases, which are precursors for hepatic inflammatory disease, cirrhosis and hepatocellular carcinoma. We have also screened ~200,000 compounds to identify small molecule inhibitors of the SREBP gene activation mechanism, and are currently characterizing lead compounds in vitro and in vivo as potential novel therapeutics for cholesterol/lipid disorders and type 2 diabetes.

  2. MicroRNA regulation of cholesterol/lipid homeostasis. Cholesterol and lipids are trafficked in the blood as lipoprotein particles, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), which ferry their fatty cargo to different cells and tissues. Intriguingly, we have found conserved microRNAs (miR-33a/b) embedded within intronic sequences in the human SREBP genes. Our studies yielded the surprising finding that miR-33a/b target the cholesterol efflux pump ABCA1 for translational repression. ABCA1 is important for HDL synthesis and reverse cholesterol transport (RCT) from peripheral tissues, including macrophages/foam cells, and mutations/single nucleotide polymorphisms in the ABCA1 gene have been implicated in atherosclerosis. Moreover, our work has shown that miR-33a/b also control the expression of genes involved in fatty acid beta-oxidation, as well as the regulation of energy homeostasis (e.g., IRS2, AMPK and SIRT6). These results demonstrate that miR-33a/b and their SREBP host genes act in concert to regulate cellular and animal metabolic homeostasis. Our findings suggest that miR-33a/b may represent novel targets of antisense-based therapeutics to increase ABCA1 levels, promote macrophage/foam cell cholesterol efflux, stimulate de novo HDL production and RCT, and ameliorate atherosclerosis/cardiovascular disease (Najafi-Shoushtari et al. Science 2010; Rottiers et al. CSH Symp Quant Biol 2012; Rottiers et al. Science Transl. Medicine 2013). We have also leveraged GWAS meta-analysis data from >188,000 individuals linking SNPs to abnormal circulating cholesterol/lipids (Willer et al. Nature Genet. 2013) to identify novel cholesterol/lipid-regulating microRNAs that may be causally related to the SNP profiles, and which may indeed provide new therapeutic strategies to treat or prevent cardiovascular disease and type 2 diabetes (Wagschal et al. Nature, 2014 under revision).

References.

1. Yang, F, Vought, BW, Satterlee, JS, Walker, AK, Sun, Z-YJ, Watts, JL, DeBeaumont, R, Saito, RM, Hyberts, SG, Yang, S, Macol, C, Iyer, L, Tjian, R, van den Heuvel, S, Hart, AC, Wagner, G, and Näär, AM. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 2006. 442:700-704.

2. Morris, EJ, Ji, J-Y, Yang, F, Di Stefano, L, Herr, A, Moon, N-S, Kwon, EJ, Haigis, KM, Näär, AM, and Dyson, NJ. E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. Nature 2008. 455:552-556. PMCID: PMC3148807

3. Najafi-Shoushtari, SH, Kristo, F, Li, X, Shioda, T, Cohen, DE, Gerszten, RE, and Näär, AM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010. 328:1566-1569. PMCID:
PMC3840500

4. Walker, AK, Yang, F, Jiang, K, Ji, J-Y, Watts, JL, Purushotham, A, Boss, O, Hirsch, ML, Ribish, S, Smith, JJ, Israelian, K, Westphal, CH, Rodgers, JT, Shioda, T, Mulligan, P, Di Stefano, L, Najafi-Shoushtari, H, Thakur, JK, Black, J, Kadyk, LC, Whetstine, J, Mostoslavsky, R, Puigserver, P, Li, X, Dyson, NJ, Hart, AC, and Näär, AM. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes & Development 2010. 24:1403-1417. PMCID: PMC2895199

5. Di Stefano, L, Walker, JA, Burgio, G, Corona, D, Mulligan, P, Näär, AM, and Dyson, NJ. Functional antagonism between histone H3K4 demethylases in vivo. Genes & Development 2011. 25:17-28. PMCID:
PMC3012933

6. Mulligan, P, Yang, F, Di Stefano, L, Ji, JY, Ouyang, J, Nishikawa, J, Wang, Q, Kulkarni, M, Najafi-Shoushtari, SH, Mostoslavsky, R, Gygi, SP, Gill, G, Dyson, NJ, and Näär, AM. A SIRT1-LSD1 co-repressor complex regulates Notch target gene expression and development. Molecular Cell 2011, 42:689-99. PMCID:
PMC3119599

7. Walker, AK, Jacobs, RL, Watts, JL, Rottiers, V, Jiang, K, Finnegan, DM, Shioda, T, Hansen, M, Yang, F, Niebergall, L, Vance, D, Tzoneva, M, Hart, AC, and Näär, AM. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 2011. 147:840-852. PMCID: PMC3384509

8. Rottiers, V, and Näär, AM. MicroRNAs in Metabolism and Metabolic Disorders. Nature Reviews Molecular Cell Biology 2012. 13:239-250. PMCID: PMC4021399

 

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