De novo lipogenesis is essential for platelet production in humans

Kelly, Kenneth L.; Reagan, William J.; Sonnenberg, G. E.; Clasquin, Michelle; Hales, Katherine; Asano, Shoh; Amor, Paul A.; Carvajal‐Gonzalez, Santos; Shirai, Norimitsu; Matthews, Marcy; Li, Kelvin W.; Hellerstein, Marc K.; Vera, Nicholas B.; Ross, Trenton T.; Cappon, Gregg D.; Bergman, Arthur; Buckeridge, Clare; Qejvanaj, Enida Ziso; Schmahai, Theodore J.; Beebe, David A.; Pfefferkorn, Jeffrey A.; Esler, William P.

doi:10.1038/s42255-020-00272-9

Cited by 30 publications

(37 citation statements)

References 57 publications

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“…Novel mechanistic studies have revealed a critical role for DNL in platelet formation 17 and sebum production in humans, 13 suggesting that DNL inhibition with systemic agents may lead to non‐hepatic effects such as thrombocytopenia, 17 dry skin and alopecia 12 . While in vitro studies have demonstrated platelet production blockage with pharmacological inhibition of ACC and FASN, 17 we did not find a reduction in platelet count in Study 2 or in human subjects receiving FT‐4101 at doses of up to 27 mg for 14 days. Differences between the two compounds in tissue distribution, the degree of DNL inhibition, continuous versus intermittent dosing and inhibition of different steps of the DNL pathway may all contribute to these discrepant effects on platelets in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, ACC and DNL inhibition in hepatic stellate cells reduced profibrogenic activity, collagen production and fibrosis, indicating a direct role of DNL in hepatic stellate cell activation 15 . Unexpected safety issues, however, such as elevated circulating triglycerides (TGs) and reductions in platelet count observed with certain ACC inhibitors have impacted their clinical development 10,11,16,17 …”

Section: Introductionmentioning

confidence: 99%

“…15 Unexpected safety issues, however, such as elevated circulating triglycerides (TGs) and reductions in platelet count observed with certain ACC inhibitors have impacted their clinical development. 10,11,16,17 Another key enzyme in the DNL pathway, FASN, catalyses the final step of DNL, converting acetyl-CoA and malonyl-CoA to palmitate. FASN gene expression level is elevated in NAFLD patients 18 and preliminary clinical data demonstrate DNL inhibition with FASN inhibition in subjects with metabolic syndrome without elevating circulating TGs.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of fatty acid synthase with FT‐4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non‐alcoholic fatty liver disease: Results from two early‐phase randomized trials

Beysen

Schroeder

et al. 2020

Diabetes Obesity Metabolism

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Aims To assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT‐4101, a potent, selective, orally bioavailable, small‐molecule by (a) evaluating the dose−response of single FT‐4101 doses (3, 6 and 9 mg) on hepatic de novo lipogenesis (DNL) in healthy participants (Study 1) and (b) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks of FT‐4101 dosing in patients with non‐alcoholic fatty liver disease (NAFLD; Study 2). Materials and Methods In Study 1, three sequential cohorts of healthy men (n = 10/cohort) were randomized to receive a single dose of FT‐4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13C‐acetate incorporation. In Study 2, men and women with NAFLD (n = 14) randomly received 12 weeks of intermittent once‐daily dosing (four cycles of 2 weeks on‐treatment, followed by 1 week off‐treatment) of 3 mg FT‐4101 (n = 9) or placebo (n = 5). Steady‐state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging‐proton density fat fraction and sebum lipids and circulating biomarkers were assessed. Results Single and repeat dosing of FT‐4101 were safe and well tolerated. Single FT‐4101 doses inhibited hepatic DNL dose‐dependently. Twelve weeks of 3 mg FT‐4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT‐4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose and lipid metabolism were unchanged. Conclusions Inhibition of FASN with 3 mg FT‐4101 safely reduces hepatic DNL and steatosis in NAFLD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of fatty acid synthase with FT‐4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non‐alcoholic fatty liver disease: Results from two early‐phase randomized trials

Beysen

Schroeder

et al. 2020

Diabetes Obesity Metabolism

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“…AMPK exerts effects on multiple pathways critical for regulating cell growth and proliferation [ 49 ]; however, cell division and proliferation are ultimately dependent on the generation of new cellular membranes, which requires de novo synthesis of fatty acids and cholesterol. This regulation of fatty acid and cholesterol synthesis has been shown to be important for dividing cancer cells [ 50 , 51 ] but also many immune cell types, including macrophages, T cells and platelets [ [52] , [53] , [54] ]. Previous studies conducted in cancer cells have shown that salicylate-induced suppression of cellular proliferation requires the inhibition of fatty acid and cholesterol synthesis [ 40 ]; therefore, we hypothesized that a similar mechanism of action may be important for mediating the anti-proliferative actions of salicylate in macrophages.…”

Section: Resultsmentioning

confidence: 99%

Salsalate reduces atherosclerosis through AMPKβ1 in mice

Day

Ford

Smith

et al. 2021

Molecular Metabolism

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Objective Salsalate is a prodrug of salicylate that lowers blood glucose in people with type 2 diabetes. AMP-activated protein kinase (AMPK) is an αβγ heterotrimer which inhibits macrophage inflammation and the synthesis of fatty acids and cholesterol in the liver through phosphorylation of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), respectively. Salicylate binds to and activates AMPKβ1-containing heterotrimers that are highly expressed in both macrophages and liver, but the potential importance of AMPK and ability of salsalate to reduce atherosclerosis have not been evaluated. Methods ApoE −/− and LDLr −/− mice with or without (−/−) germline or bone marrow AMPKβ1, respectively, were treated with salsalate, and atherosclerotic plaque size was evaluated in serial sections of the aortic root. Studies examining the effects of salicylate on markers of inflammation, fatty acid and cholesterol synthesis and proliferation were conducted in bone marrow–derived macrophages (BMDMs) from wild-type mice or mice lacking AMPKβ1 or the key AMPK-inhibitory phosphorylation sites on ACC (ACC knock-in (KI)-ACC KI) or HMGCR (HMGCR-KI). Results Salsalate reduced atherosclerotic plaques in the aortic roots of ApoE −/− mice, but not ApoE −/− AMPKβ1 −/− mice. Similarly, salsalate reduced atherosclerosis in LDLr −/− mice receiving wild-type but not AMPKβ1 −/− bone marrow. Reductions in atherosclerosis by salsalate were associated with reduced macrophage proliferation, reduced plaque lipid content and reduced serum cholesterol. In BMDMs, this suppression of proliferation by salicylate required phosphorylation of HMGCR and the suppression of cholesterol synthesis. Conclusions These data indicate that salsalate suppresses macrophage proliferation and atherosclerosis through an AMPKβ1-dependent pathway, which may involve HMGCR phosphorylation and cholesterol synthesis. Since rapidly-proliferating macrophages are a hallmark of atherosclerosis, these data indicate further evaluation of salsalate as a potential therapeutic agent for treating atherosclerotic cardiovascular disease.

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“…Unlike in macrophage, where oxLDL elevates the expression of both PPARα 21 and PPARγ, 39 megakaryocytes seems to respond to hyperlipidemia specifically with an up-regulated expression of PPARα, but not that of PPARβ or PPARγ. Considering the importance of fatty 21 acids in supporting both megakaryocyte maturation 40 and platelet production, 41 and the central roles of PPARα in fatty acids metabolism, 17,42 it may not be surprising that megakaryocyte PPARα is a sensitive and specific target regulated by hyperlipidemia.…”

Section: Discussionmentioning

confidence: 99%

Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia

Wang

Jiang

et al. 2021

haematol

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Platelet hyperreactivity and increased atherothrombotic risk are specifically associated with dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARα) is an important regulator of lipid metabolism. It was suggested to affect both thrombosis and hemostasis, yet the underlying mechanisms are not well understood. In this study, the role and mechanism of PPARα in platelet activation and thrombosis related to dyslipidemia were examined. Employing mice with deletion of PPARα (Pparα -/-), we demonstrated that PPARα is required for platelet activation and thrombus formation. The effect of PPARα is critically dependent on platelet dense granule secretion, and is contributed by p38MAPK/Akt, fatty acid β- oxidation, and NAD(P)H oxidase (NOX) pathways. Importantly, PPARα and the associated pathways mediated a prothrombotic state induced by high-fat diet (HFD) and platelet hyperactivity provoked by oxidized low density lipoproteins (oxLDL). Platelet reactivities were positively correlated with the expression levels of PPARα, as revealed by data from wild-type (WT), chimeric (Pparα +/-), and Pparα -/- mice. This positive correlation was recapitulated in platelets from hyperlipidemic patients. In a lipid-treated megakaryocytic cell line, lipid-induced reactive oxygen species (ROS)-NF-κB pathway was revealed to upregulate platelet PPARα in hyperlipidemia. These data suggested platelet PPARα critically mediates platelet activation and contributes to prothrombotic status under hyperlipidemia.

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De novo lipogenesis is essential for platelet production in humans

Cited by 30 publications

References 57 publications

Inhibition of fatty acid synthase with FT‐4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non‐alcoholic fatty liver disease: Results from two early‐phase randomized trials

Inhibition of fatty acid synthase with FT‐4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non‐alcoholic fatty liver disease: Results from two early‐phase randomized trials

Salsalate reduces atherosclerosis through AMPKβ1 in mice

Critical role of peroxisome proliferator-activated receptor α in promoting platelet hyperreactivity and thrombosis under hyperlipidemia

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