Professor of Metabolic Biology
About Anders Näär
Anders M. Näär is a Professor of Metabolic Biology in the Department of Nutritional Sciences & Toxicology at the University of California, Berkeley. He received a B.S. degree in biochemistry/biotechnology from the University of Lund, Sweden, in 1988, and a Ph.D. in Molecular Pathology with M. Geoff Rosenfeld at UC San Diego/HHMI in 1995, studying nuclear hormone receptor mechanisms of gene regulation. He was a postdoctoral research fellow with Robert Tjian at UC Berkeley/HHMI, where he discovered the human Mediator transcriptional co-activator complex. Dr. Näär was a Professor in the Department of Cell Biology, Harvard Medical School and the Massachusetts General Hospital Cancer Center, from 2001-2018.
A major focus of his lab is to understand transcriptional and microRNA regulatory mechanisms controlling metabolic homeostasis to guide novel therapeutic strategies for the treatment of cardiovascular disease, obesity, Type 2 diabetes, non-alcoholic fatty liver diseases (NAFLD/NASH), age-related macular degeneration (AMD), Duchenne muscular dystrophy (DMD), multi-drug resistant fungal infections, and numerous types of cancer.
The primary focus of the Näär lab is to elucidate transcriptional and microRNA regulatory mechanisms governing cholesterol/lipid and metabolic homeostasis. Our studies over the last 20 years of the sterol- regulatory element-binding protein (SREBP) family of transcription factors, master regulators of cholesterol/lipid synthesis and trafficking, have led to an atomic-level understanding of the molecular mechanism of SREBP gene regulation. We have parlayed this detailed mechanistic knowledge to guide small molecule therapeutic targeting efforts resulting in the development of nanomolar inhibitors of the interaction of SREBPs with transcriptional co-activators. Ongoing NMR structure-guided medicinal chemistry efforts are aimed at further improving on these inhibitors, with the goal of identifying effective therapeutic modalities as treatments for diseases linked to abnormal cholesterol/lipids and metabolism, including many types of cancers, as well as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our work is innovative as it challenges the prevalent dogma that protein-protein interactions are not druggable.
Our studies have also identified microRNAs as crucial regulators of cholesterol/lipids and metabolism. We uncovered miR-33a/b as intronic microRNAs present in the SREBP genes that act in concert with the host genes to govern cholesterol/lipid homeostasis. Based on potent effects of antisense oligonucleotides (ASOs) targeting miR-33a/b on atherosclerosis in rodent models, we are currently pursuing state-of-the art locked nucleic acid (LNA) ASO technologies as novel and safe treatments for familial hypercholesterolemia and other cardiovascular diseases, as well as age-related macular degeneration (AMD).
Employing genome-wide association study data from >188,000 individuals we have identified a microRNA, miR-128-1, as a crucial regulator of circulating cholesterol and triglycerides. Surprisingly, miR-128- 1 is located in a genomic region on human chromosome 2 that is also strongly linked to recent positive selection, type 2 diabetes, and obesity. Based on our supportive in vivo data in several mouse obesity and metabolic disease models, we hypothesize that miR-128-1 represents a thrifty microRNA that acts as a potent negative regulator of energy expenditure, selected as a human evolutionary adaptation to promote fat storage to survive famine in ancient times. Currently, this represents a maladaptation in the developed world with abundant food, resulting in increased risk for cardio-metabolic diseases such as coronary artery disease, Metabolic Syndrome (MetS), obesity, type 2 diabetes, and non-alcoholic fatty liver diseases (NAFLD/NASH). Indeed, our ongoing and planned studies are aimed at developing LNA ASO modalities targeting miR-128-1 for the treatment of these metabolic diseases, and unpublished results from mouse obesity and NASH models look very promising. We have also unexpectedly found a link of miR-128-1 to Duchenne Muscular Dystrophy (DMD), a rare and early lethal muscle wasting disorder, and we are investigating a potential pathological disease modifying role of miR-128-1 in DMD, and whether it might represent a target for LNA ASOs as a novel DMD treatment in conjunction with other approaches such as exon-skipping ASO modalities.
Altogether, we are taking advantage of deep insights into molecular underpinnings of common and rare human diseases gained from our mechanistic studies to develop novel therapeutic targeting strategies.
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 atherosclerosis, type 2 diabetes, metabolic syndrome, 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 multiprotein 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). We 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 together may yield novel treatments for cardiometabolic diseases and cancers.
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 revealed 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 in the ABCA1 gene have been implicated in atherosclerosis. These findings suggest that miR-33a/b may represent novel targets of antisense-based therapeutics to ameliorate cardiovascular disease (Najafi-Shoushtari et al. Science 2010; Rottiers et al. CSH Symp Quant Biol 2012; Rottiers & Näär, Nature Rev Mol Cell Biol 2012; Rottiers et al. Science Translational Medicine 2013). We have pioneered a systematic and multi- pronged approach to comprehensively determine the roles of microRNAs and other noncoding RNAs in metabolic control and contribution to cardiometabolic diseases. Our analysis of GWAS in >188,000 people uncovered several microRNAs associated with cardiometabolic abnormalities. We have demonstrated that two of these microRNAs, miR-128-1 and miR-148a, control HDL-cholesterol and low-density lipoprotein-cholesterol (LDL-C) through direct regulation of ABCA1 and LDL receptor (LDLR) expression, respectively. Moreover, our in vivo studies show that LNA antimiRs directed against these microRNAs led to upregulation of the LDLR and ABCA1 in liver, with a concomitant beneficial decrease in circulating LDL-C and increased HDL-C. Results from these studies indicate that microRNAs may indeed represent novel therapeutic targets for the treatment of cardiovascular disease (Wagschal et al., Nature Medicine 2015; Goedeke et al., Nature Medicine 2015).
Multidrug resistance in pathogenic fungi
Immunocompromised individuals, such as cancer patients undergoing chemotherapy are highly susceptible to fungal infections (e.g., Candida species), which frequently become drug-resistant upon antifungal treatment. We have elucidated the molecular mechanism by which the important human pathogenic fungus Candida glabrata becomes resistant to standard azole antifungal treatment (Thakur et al. Nature 2008). Our work has led to the identification of a potent inhibitor of multidrug resistance (MDR) in C. glabrata. This compound exhibits efficacy in mouse models as a novel anti-MDR co-therapeutic to re-sensitize drug-resistant C. glabrata to standard azole treatment (Nishikawa et al. Nature 2016).
Chery, J, Petri, A, Wagschal, A, Lim, SY, Cunningham, J, Vasudevan, S, Kauppinen, S, Näär, AM. Development of Locked Nucleic Acid antisense oligonucleotide therapeutics targeting Ebola proteins and host factor NPC1. Nucleic Acid Therapeutics (in press).
Näär, AM. miR-33: a metabolic conundrum. Trends in Endocrinology and Metabolism. 2018 Apr 21. pii: S1043-2760(18)30087-0. doi: 10.1016/j.tem.2018.04.004. Invited Spotlight review.
Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, Ji F, Gelev V, Sanglard D, Sanguinetti M, Sadreyev RI, Buhrlage SJ, Gray NS, Wagner G*, Näär AM*, and Arthanari H*. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016 Feb 25;530(7591):485-9. *Co-corresponding authors. Highlighted in Nature Reviews Drug Discovery.
Lai, L, Azzam, KM, Lin, WC, Rai, P, Lowe, JM, Gabor, KA, Madenspacher, JH, Aloor, JJ, Parks, JS, Näär, AM, and Fessler, MB. MicroRNA-33 regulates the innate immune response via ATP Binding Cassette transporter-mediated remodeling of membrane microdomains. Journal of Biological Chemistry. 2016. 291:19651-60.
Wagschal A, Najafi-Shoushtari SH, Wang L, Goedeke L, Sinha S, Delemos AS, Black JC, Ramirez CM, Li X, Tewhey R, Hatoum I, Shah N, Kristo F, Psychogios N, Vrbanac V, Lu Y-C, Hla T, de Cabo R, Tsang JS, Schadt E, Sabeti PC, Kathiresan S, Cohen DE, Whetstine J, Chung RT, Fernández- Hernando C, Kaplan LM, Bernards A, Gerszten RE, and Näär, AM. Genome-wide identification of microRNAs regulating cholesterol/ lipid homeostasis. Nature Medicine. 2015 Nov;21(11):1290-7. Highlighted as top 10 paper in cardiovascular research 2015 by the American Heart Association.
Goedeke L, Aranda JF, Canfrán-Duque A, Rotllan N, Ramírez CM, Lin C-S, Araldi E, Anderson NN, Wagschal
A, Cabo RD, Horton JD, Lasunción MA, Näär, AM, Suárez Y and Fernández-Hernando C. Identification of miR-148a as a novel regulator of cholesterol metabolism. Nature Medicine. 2015 Nov;21(11):1280-9.
Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Dake B, Glover E, Richardson A, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Näär, AM, Blasco MA, Hinds PW, and Kuper- wasser C. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nature Communications. 2015 Jun 24;6:7505.
Rottiers V, Obad S, Petri A, McGarrah R, Lindholm MW, Black JC, Sinha S, Goody RJ, Lawrence MS, Delemos AS, Hansen HF, Whittaker S, Henry S, Brookes R, Najafi-Shoushtari SH, Chung RT, Whetstine JW, Gerszten RE, Kauppinen S*, and Näär, AM*. Pharmacological inhibition of a microRNA family in non-human primates by a seed-targeting 8-mer antimiR oligonucleotide. Science Translational Medicine. 2013 Nov 20;5(212):212ra162. Highlighted in NIH Director’s blog. *Co-corresponding authors.
Toiber, D, Erdel, F, Silberman, D, Zhong, L, Mulligan, P, Bouazoune, K, Sebastian, C, Cosentino, C, Martinez-Pastor, B, Giacosa, S, D'Urso, A, Näär, AM, Kingston, R, Rippe, K, and Mostoslavsky, R. SIRT6 recruits SNF2H to sites of DNA breaks, preventing genomic instability through chromatin remodeling. Molecular Cell. 2013. 51:454-468.
Rottiers, V, and Näär, AM. MicroRNAs in Metabolism and Metabolic Disorders. Nature Reviews Molecular Cell Biology. 2012. 13:239-250.
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. Immediate early publication Oct. 27, 2011. Highlighted in Cell (Preview), and in Science Signaling (Editor’s Choice). Faculty 1000 Cell Biology: 6.0 (Recommended).
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. Epub May 18, 2011 ahead of print. Highlighted in Molecular Cell (Preview).
Milbradt, AG, Kulkarni, M, Yi, T, Takeuchi, K, Sun, Z-Y, Luna, R, Selenko, P, Näär, AM*, and Wagner, G*. Structure of the VP16 transactivator target in the Mediator. Nature Structural & Molecular Biology. 2011. 18:410-415. (Epub ahead of print March 6, 2011). *Co-corresponding authors.
Rottiers, V, Najafi-Shoushtari, SH, Kristo, F, Gurumurthy, S, Zhong, L, Li, Y, Cohen, DE, Gerszten, RE, Bardeesy, N, Mostoslavsky, R, and Näär, AM. MicroRNAs in Metabolism and Metabolic Diseases. CSH Symposia on Quantitative Biology: Metabolism & Disease. 2011. 76: 225-233.
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.
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.
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 (Advance Online Publication May 13, 2010). Highlighted in Science (Perspective), Science Signaling, Nature Medicine, Nature Genetics, Nature Reviews Drug Discovery, and JAMA. Faculty 1000 Biology: 8.0 (Exceptional).
Näär, AM* and Thakur, JK. Nuclear Receptor-Like Transcription Factors in Fungi. Review. Genes & Development. 2009. 23:419-432. *Corresponding author.
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. Highlighted in Nature (News & Views).
Thakur, JK, Arthanari, H, Yang, F, Pan, S-J, Fang, X, Breger, J, Frueh, DP, Gulshan, K, Li, DK, Mylonakis, E, Struhl, K, Moye-Rowley, WS, Cormack, B, Wagner, G, and Näär, AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature [Article] 2008. 452:604-609. Highlighted in Nature (News & Views) and Science (Perspective). Faculty 1000 Biology: 9.8 (Exceptional).
Binné, UK, Classon, MK, Dick, FA, Wei, W, Rape, M, Kaelin, WG, Näär, AM*, and Dyson, NJ*. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nature Cell Biology. 2007. 9:225-232 (Advance Online Publication, Dec. 24, 2006). *Co-corresponding authors. Highlighted in Nature Cell Biology and Developmental Cell. Faculty 1000 Biology: 6.0 (Must Read).
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 (Advance Online Publication, June 21st, 2006). Highlighted in Nature News & Views, Cell Metabolism, and JAMA.
Baillat, D, Hakimi, MA, Näär, AM, Shilatifard, A, Cooch, N, and Shiekhattar, R. Integrator, a multiprotein mediator of small nuclear RNA processing associates with the C-terminal repeat of RNA polymerase II. Cell. 2005. 123:265-276. Faculty 1000 Biology: 3.0 (Recommended).
Bourbon, HM, Aguilera, A, Ansari, AZ, Asturias, FJ, Berk, AJ, Bjorklund, S, Blackwell, TK, Borggrefe, T, Carey, M, Carlson, M, Conaway, JW, Conaway, RC, Emmons, SW, Fondell, JD, Freedman, LP, Fukasawa, T, Gustafsson, CM, Han, M, He, X, Herman, PK, Hinnebusch, AG, Holmberg, S, Holstege, FC, Jaehning, JA, Kim, YJ, Kuras, L, Leutz, A, Lis, JT, Meisterernest, M, Näär, AM, Nasmyth, K, Parvin, JD, Ptashne, M, Reinberg, D, Ronne, H, Sadowski, I, Sakurai, H, Sipiczki, M, Sternberg, PW, Stillman, DJ, Strich, R, Struhl, K, Svejstrup, JQ, Tuck, S, Winston, F, Roeder, RG, Kornberg, RD. A unified nomenclature for protein subunits of Mediator complexes linking transcriptional regulators to RNA polymerase II. Molecular Cell. 2004. 14:553-557.
Yang, F, DeBeaumont, R, Zhou, S, and Näär, AM. The activator-recruited cofactor/Mediator co-activator subunit ARC92 is a functionally important target of the VP16 transcriptional activator. Proc. Natl. Acad. Sci. USA. 2004. 101:2339-2344.
Kato, Y., Habas, R., Katsuyama, Y, Näär, AM, and He, X. A component of the ARC/Mediator complex required for TGF-ß/Nodal signaling. Nature. 2002. 418:641-646.
Honors and Awards
1988-1990 California Fellowship; Education Abroad Program; University of Lund (Sweden) and UC San Diego
1992 Award; Paulsen Foundation at UC San Diego; Research
1992-1993 Fellowship; Sweden-America Foundation; Scientific and research exchange
1995-1998 Postdoctoral Fellowship; Damon Runyon-Walter Winchell Cancer Foundation; Cancer research
2003 Scholar; Dennis and Marsha Dammerman Scholar Award; Damon Runyon Cancer Research Foundation; Cancer research
2012 Scholar; Massachusetts General Hospital Research Scholar Award; Cholesterol research
2015 Award; Research to Prevent Blindness; Stein Innovation Award; Eye disease research
2017 Scholar; Massachusetts General Hospital Research Scholar Award; Cholesterol and microRNA research