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De novo lipogenesis is essential for platelet production in humans

Nature Metabolism volume 2, pages 1163–1178 (2020)Cite this article

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Abstract

Acetyl-CoA carboxylase (ACC) catalyses the first step of de novo lipogenesis (DNL). Pharmacologic inhibition of ACC has been of interest for therapeutic intervention in a wide range of diseases. We demonstrate here that ACC and DNL are essential for platelet production in humans and monkeys, but in not rodents or dogs. During clinical evaluation of a systemically distributed ACC inhibitor, unexpected dose-dependent reductions in platelet count were observed. While platelet count reductions were not observed in rat and dog toxicology studies, subsequent studies in cynomolgus monkeys recapitulated these platelet count reductions with a similar concentration response to that in humans. These studies, along with ex vivo human megakaryocyte maturation studies, demonstrate that platelet lowering is a consequence of DNL inhibition likely to result in impaired megakaryocyte demarcation membrane formation. These observations demonstrate that while DNL is a minor quantitative contributor to global lipid balance in humans, DNL is essential to specific lipid pools of physiological importance.

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Fig. 1: Administration of PF-05175157 reversibly and dose-dependently lowered platelet count in healthy human participants.
Fig. 2: Airyscan confocal imaging characterizing ex vivo cord-blood-derived human MK culture system on day 12 of culture.
Fig. 3: ACC inhibition decreases platelet production in human MKs in vitro.
Fig. 4: DNL is required for late-stage MK maturation and platelet formation.
Fig. 5: Large, surface-complex MKs (high SSC) are decreased from the mature population in ACC inhibitor-treated cells.
Fig. 6: ACC inhibitor treatment blocks DNL and reduces PCs composed of DNL-derived fatty acids.
Fig. 7: Decreased platelets and effect on bone marrow MK after administration of ACC inhibitors to monkeys.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Expression data for murine and human megakaryocytes were obtained from the European Bioinformatics Institute Gene Expression Atlas. For murine megakaryocytes RNA-seq data from experiment E-MTAB-3079 (ref. 59) were obtained. For human megakaryocytes data from experiment E-MTAB-3827 (ref. 60) were obtained. Source data and the relevant protocols can be found at: https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3079/ and https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3827/.

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Acknowledgements

We thank D. Griffith, A. Smith and K. Huard for assistance in sourcing the ACC and FASN inhibitors for testing; E. Pashos for compiling the lipogenic enzyme expression data in rodent and human MKs; and G. El Sebae for help with staining MK cell preparations. We also thank M. Birnbaum for helpful discussions. This work was funded by Pfizer Inc.

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Authors and Affiliations

  1. Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA

    Kenneth L. Kelly, Michelle Clasquin, Katherine Hales, Shoh Asano, Paul A. Amor, Nicholas B. Vera, Trenton T. Ross, Clare Buckeridge, Zhongyuan Sun, Enida Ziso Qejvanaj, David Beebe, Jeffrey A. Pfefferkorn & William P. Esler

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    William J. Reagan, Norimitsu Shirai, Gregg Cappon & Theodore Schmahai

  3. Early Clinical Development, Pfizer Worldwide Research and Development, Cambridge, MA, USA

    Gabriele E. Sonnenberg, Santos Carvajal-Gonzalez & Arthur Bergman

  4. Department of Nutritional Sciences and Toxicology, University of California at Berkeley, Berkeley, CA, USA

    Marcy D. Matthews, Kelvin W. Li & Marc K. Hellerstein

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  1. Kenneth L. Kelly
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Contributions

K.L.K. designed and conducted the ex vivo studies and flow cytometry and interpretation of data. G.E.S., S.C.-G., A.B. and C.B. designed and oversaw clinical studies and analysed clinical data. S.C.-G. also conducted statistical analysis for clinical and ex vivo studies. W.J.R., G.C., T.S. and N.S. designed and oversaw nonhuman primate studies and interpretation of nonhuman primate data. K.L.K., K.H. and S.A. conducted florescence confocal microscopy studies. N.S. contributed to electron microscopy studies. M.C., N.B.V., Z.S. and E.Z.Q. conducted lipidomic analysis. M.C., M.D.M., K.W.L. and M.K.H. contributed to design, conduct, analysis and interpretation of stable isotope studies. P.A.A., T.T.R. and D.B. contributed to ex vivo study design, conduct and interpretation. J.A.P. contributed to study conceptualization and interpretation. W.P.E. conceived, designed and supervised the project; contributed to study design; interpreted data; and wrote the manuscript. K.L.K., W.J.R., G.E.S., M.C., K.W.L. and M.K.H. also contributed to writing the manuscript. All authors contributed to data interpretation and critical review of the manuscript.

Corresponding author

Correspondence to William P. Esler.

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Competing interests

K.L.K., W.J.R., M.C., K.H., S.A., P.A.A., S.C.-G., N.S., N.B.V., T.T.R., G.C., A.B., C.B., Z.S., E.Z.Q., T.S., J.A.P. and W.P.E. are employees and may be shareholders of Pfizer Inc. G.E.S. and D.B. were employees of Pfizer at the time these studies were conducted and may be shareholders of Pfizer Inc. M.K.H. is a consultant to Pfizer Inc.

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Extended data

Extended Data Fig. 1 Platelet counts in 4-month oral toxicity studies of PF-05175157 in rats and dogs.

a, platelet counts in male and female Wistar Han rats on day 118. N=10 per group. Wistar Han rats were from Charles River Laboratories 8–9 wks old. b, platelet counts in male and female dogs during pre-study (day -13) and day 114. N=3 per sex per group. Dogs were Beagles (male and female) from Marshal Farms > 8 months old. Data are mean ± standard deviation. Symbols represent individual values.

Extended Data Fig. 2 May-Grünwald Giemsa stained megakaryocytes from ex vivo cultures.

Cytospun slides were prepared from in vitro cultures of megakaryocytes on day 12 of culture. All photos were taken at the same magnification (100x oil) and the scale bars shown on images a and c represent 10 microns. a. Low polyploid megakaryocyte (4N) (arrowhead). b, c, Large cells with multilobulated nuclei and granular cytoplasm are mature megakaryocytes (arrows) (≥16N).

Extended Data Fig. 3 DMS continuity between vehicle and ACCi (10µM) treated groups in lower polyploid MKs.

Megakaryocytes differentiated from bone marrow derived CD34+ cells were utilized to visualize internal DMS continuity between vehicle and ACCi (10µM) treated groups in lower polyploid cells on day 13 of culture (Scale bars=10µm, green= CD41a-FITC/ DMS, Red=α-tubulin, blue=DNA/ DAPI) (left quad panels are 2D images from a single, z-stack optical slice; right enlarged image is a 3D render of the same cell through a similar plane). a, vehicle treated low polyploid MK exhibiting highly contiguous DMS (green) throughout the cytoplasmic volume. b, ACCi treated (10µM) lower polyploid MK showing an apparent reduction with discontinuous and diffuse with less structurally defined DMS staining (green). The 3D merged rendered movies of these cells are available as Supplemental Videos 3–4.

Extended Data Fig. 4 Expression of lipogenic genes in murine and human megakaryocytes.

Expression data for murine and human megakaryocytes were obtained from the European Bioinformatics Institute (EBI) Gene Expression Atlas. For murine megakaryocytes a, RNAseq data from experiment E-MTAB-307959 from were obtained. Mice were C57BL/6J mice between 4–6 weeks of age. Data represent one biological experiment. For human megakaryocytes b, data from experiment E-MTAB-382760 were obtained. Boxplots of the human megakaryocyte samples (n=2) were produced using the ggplot2 library in R. The lower hinge of the boxplot represents the lower of the two expression values and the higher hinge of the boxplot represent the higher of the two values. Normalized expression values of ACC and FASN were higher in human megakaryocytes compared to their murine counterparts. Source data and the relevant protocols can be found at: https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3079/ and https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3827/.

Supplementary information

Supplementary Information

Supplementary Figs. 1–4 and Tables 1–3

Reporting Summary

Supplementary Video 1

Video of vehicle-treated high-ploidy MK cell from Fig. 5c

Supplementary Video 2

Video of ACCi-treated high-ploidy MK cell from Fig. 5d

Supplementary Video 3

Video of vehicle-treated lower-ploidy MK cell from Extended Data Fig. 3a

Supplementary Video 4

Video of ACCi-treated lower-ploidy MK cell from Extended Data Fig. 3b

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Kelly, K.L., Reagan, W.J., Sonnenberg, G.E. et al. De novo lipogenesis is essential for platelet production in humans. Nat Metab 2, 1163–1178 (2020). https://doi.org/10.1038/s42255-020-00272-9

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