Brian T Palmisano

All Publications

• Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk. Arteriosclerosis, thrombosis, and vascular biology Quertermous, T., Li, D. Y., Weldy, C. S., Ramste, M., Sharma, D., Monteiro, J. P., Gu, W., Worssam, M. D., Palmisano, B. T., Park, C. Y., Cheng, P. 2024; 44 (2): 323-327

  Abstract

  The goal of this review is to discuss the implementation of genome-wide association studies to identify causal mechanisms of vascular disease risk.The history of genome-wide association studies is described, the use of imputation and the creation of consortia to conduct meta-analyses with sufficient power to arrive at consistent associated loci for vascular disease. Genomic methods are described that allow the identification of causal variants and causal genes and how they impact the disease process. The power of single-cell analyses to promote genome-wide association studies of causal gene function is described.Genome-wide association studies represent a paradigm shift in the study of cardiovascular disease, providing identification of genes, cellular phenotypes, and disease pathways that empower the future of targeted drug development.

  View details for DOI 10.1161/ATVBAHA.123.319480

  View details for PubMedID 38266112

• Another Use for Polygenic Risk Scores: Improving Risk Prediction for Heterozygous Familial Hypercholesterolemia. JACC. Advances Palmisano, B. T., Knowles, J. W. 2023; 2 (9): 100663

  View details for DOI 10.1016/j.jacadv.2023.100663

  View details for PubMedID 38938727

  View details for PubMedCentralID PMC11198439

• Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice METABOLITES Palmisano, B. T., Zhu, L., Litts, B., Burman, A., Yu, S., Neuman, J. C., Anozie, U., Luu, T. N., Edington, E. M., Stafford, J. M. 2021; 11 (5)

  View details for DOI 10.3390/metabo11050330

  View details for Web of Science ID 000654293700001

• Low-density lipoprotein receptor is required for cholesteryl ester transfer protein to regulate triglyceride metabolism in both male and female mice. Physiological reports Palmisano, B. T., Yu, S., Neuman, J. C., Zhu, L., Luu, T., Stafford, J. M. 2021; 9 (4): e14732

  Abstract

  Elevated triglycerides (TGs) and impaired TG clearance increase the risk of cardiovascular disease in both men and women, but molecular mechanisms remain poorly understood. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein cholesterol. Although mice lack CETP, transgenic expression of CETP in mice alters TG metabolism in males and females by sex-specific mechanisms. A unifying mechanism explaining how CETP alters TG metabolism in both males and females remains unknown. Since low-density lipoprotein receptor (LDLR) regulates both TG clearance and very low density lipoprotein (VLDL) production, LDLR may be involved in CETP-mediated alterations in TG metabolism in both males and females. We hypothesize that LDLR is required for CETP to alter TG metabolism in both males and females. We used LDLR null mice with and without CETP to demonstrate that LDLR is required for CETP to raise plasma TGs and to impair TG clearance in males. We also demonstrate that LDLR is required for CETP to increase TG production and to increase the expression and activity of VLDL synthesis targets in response to estrogen. Additionally, we show that LDLR is required for CETP to enhance beta-oxidation. These studies support that LDLR is required for CETP to regulate TG metabolism in both males and females.

  View details for DOI 10.14814/phy2.14732

  View details for PubMedID 33625789

• Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice. Lipids Palmisano, B. T., Anozie, U. n., Yu, S. n., Neuman, J. C., Zhu, L. n., Edington, E. M., Luu, T. n., Stafford, J. M. 2020

  Abstract

  Elevated postprandial triacylglycerols (TAG) are an important risk factor for cardiovascular disease. Men have higher plasma TAG and impaired TAG clearance compared to women, which may contribute to sex differences in risk of cardiovascular disease. Understanding mechanisms of sex differences in TAG metabolism may yield novel therapeutic targets to prevent cardiovascular disease. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein (HDL) cholesterol levels. Although mice lack CETP, we previously demonstrated that transgenic CETP expression in female mice alters TAG metabolism. The impact of CETP on TAG metabolism in males, however, is not well understood. Here, we demonstrate that CETP expression increases plasma TAG in males, especially in very-low density lipoprotein (VLDL), by impairing postprandial plasma TAG clearance compared to wild-type (WT) males. Gonadal hormones were required for CETP to impair TAG clearance, suggesting a role for sex hormones for this effect. Testosterone replacement in the setting of gonadectomy was sufficient to restore the effect of CETP on TAG. Lastly, liver androgen receptor (AR) was required for CETP to increase plasma TAG. Thus, expression of CETP in males raises plasma TAG by impairing TAG clearance via testosterone signaling to AR. Further understanding of how CETP and androgen signaling impair TAG clearance may lead to novel approaches to reduce TAG and mitigate risk of cardiovascular disease.

  View details for DOI 10.1002/lipd.12271

  View details for PubMedID 32783209

• Sex differences in lipid and lipoprotein metabolism. Molecular metabolism Palmisano, B. T., Zhu, L. n., Eckel, R. H., Stafford, J. M. 2018; 15: 45–55

  Abstract

  Endogenous sex hormones are important for metabolic health in men and women. Before menopause, women are protected from atherosclerotic cardiovascular disease (ASCVD) relative to men. Women have fewer cardiovascular complications of obesity compared to men with obesity. Endogenous estrogens have been proposed as a mechanism that lessens ASCVD risk, as risk of glucose and lipid abnormalities increases when endogenous estrogens decline with menopause. While baseline risk is higher in males than females, endogenously produced androgens are also protective against fatty liver, diabetes and ASCVD, as risk goes up with androgen deprivation and with the decline in androgens with age.In this review, we discuss evidence of how endogenous sex hormones and hormone treatment approaches impact fatty acid, triglyceride, and cholesterol metabolism to influence metabolic and cardiovascular risk. We also discuss potential reasons for why treatment strategies with estrogens and androgens in older individuals fail to fully recapitulate the effects of endogenous sex hormones.The pathways that confer ASCVD protection for women are of potential therapeutic relevance. Despite protection relative to men, ASCVD is still the major cause of mortality in women. Additionally, diabetic women have similar ASCVD risk as diabetic men, suggesting that the presence of diabetes may offset the protective cardiovascular effects of being female through unknown mechanisms.

  View details for DOI 10.1016/j.molmet.2018.05.008

  View details for PubMedID 29858147

  View details for PubMedCentralID PMC6066747

• Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding. Molecular metabolism Zhu, L. n., Shi, J. n., Luu, T. N., Neuman, J. C., Trefts, E. n., Yu, S. n., Palmisano, B. T., Wasserman, D. H., Linton, M. F., Stafford, J. M. 2018; 8: 106–16

  Abstract

  Hepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported.Using LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of 3H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls.Estrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet.

  View details for DOI 10.1016/j.molmet.2017.12.012

  View details for PubMedID 29331506

  View details for PubMedCentralID PMC5985047

• High-Fat Feeding Does Not Disrupt Daily Rhythms in Female Mice because of Protection by Ovarian Hormones FRONTIERS IN ENDOCRINOLOGY Palmisano, B. T., Stafford, J. M., Pendergast, J. S. 2017; 8: 44

  Abstract

  Obesity in women is increased by the loss of circulating estrogen after menopause. Shift work, which disrupts circadian rhythms, also increases the risk for obesity. It is not known whether ovarian hormones interact with the circadian system to protect females from obesity. During high-fat feeding, male C57BL/6J mice develop profound obesity and disruption of daily rhythms. Since C57BL/6J female mice did not develop diet-induced obesity (during 8 weeks of high-fat feeding), we first determined if daily rhythms in female mice were resistant to disruption from high-fat diet. We fed female PERIOD2:LUCIFERASE mice 45% high-fat diet for 1 week and measured daily rhythms. Female mice retained robust rhythms of eating behavior and locomotor activity during high-fat feeding that were similar to chow-fed females. In addition, the phase of the liver molecular timekeeping (PER2:LUC) rhythm was not altered by high-fat feeding in females. To determine if ovarian hormones protected daily rhythms in female mice from high-fat feeding, we analyzed rhythms in ovariectomized mice. During high-fat feeding, the amplitudes of the eating behavior and locomotor activity rhythms were reduced in ovariectomized females. Liver PER2:LUC rhythms were also advanced by ~4 h by high-fat feeding, but not chow, in ovariectomized females. Together these data show circulating ovarian hormones protect the integrity of daily rhythms in female mice during high-fat feeding.

  View details for DOI 10.3389/fendo.2017.00044

  View details for Web of Science ID 000396100500001

  View details for PubMedID 28352249

  View details for PubMedCentralID PMC5348546

• Role of Estrogens in the Regulation of Liver Lipid Metabolism. Advances in experimental medicine and biology Palmisano, B. T., Zhu, L. n., Stafford, J. M. 2017; 1043: 227–56

  Abstract

  Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride, and cholesterol metabolism to influence cardiovascular risk.The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increases VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides.Many aspects of sex differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in the muscle, adipose, and liver. In humans, 17β-estradiol (E2) is the predominant circulating estrogen and signals through estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled estrogen receptor (GPER). Over 1000 human liver genes display a sex bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues or specific aspects of the signaling pathways in order to recapitulate the protective physiology of premenopause therapeutically after menopause.

  View details for DOI 10.1007/978-3-319-70178-3_12

  View details for PubMedID 29224098

  View details for PubMedCentralID PMC5763482

• Role of Estrogens in the Regulation of Liver Lipid Metabolism Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity Palmisano, B. T., Zhu, L., Stafford, J. M. Springer. 2017: 227-256

  View details for DOI https://doi.org/10.1007/978-3-319-70178-3_12

• Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice. Journal of lipid research Palmisano, B. T., Le, T. D., Zhu, L. n., Lee, Y. K., Stafford, J. M. 2016; 57 (8): 1541–51

  Abstract

  Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism.

  View details for DOI 10.1194/jlr.M069013

  View details for PubMedID 27354419

  View details for PubMedCentralID PMC4959869

• CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity. PloS one Cappel, D. A., Lantier, L. n., Palmisano, B. T., Wasserman, D. H., Stafford, J. M. 2015; 10 (8): e0136915

  Abstract

  Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

  View details for DOI 10.1371/journal.pone.0136915

  View details for PubMedID 26313355

  View details for PubMedCentralID PMC4551677

• Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. American journal of physiology. Endocrinology and metabolism Zhu, L. n., Martinez, M. N., Emfinger, C. H., Palmisano, B. T., Stafford, J. M. 2014; 306 (10): E1188–97

  Abstract

  The development of insulin resistance in the liver is a key event that drives dyslipidemia and predicts diabetes and cardiovascular risk with obesity. Clinical data show that estrogen signaling in males helps prevent adiposity and insulin resistance, which may be mediated through estrogen receptor-α (ERα). The tissues and pathways that mediate the benefits of estrogen signaling in males with obesity are not well defined. In female mice, ERα signaling in the liver helps to correct pathway-selective insulin resistance with estrogen treatment after ovariectomy. We assessed the importance of liver estrogen signaling in males using liver ERα-knockout (LKO) mice fed a high-fat diet (HFD). We found that the LKO male mice had decreased insulin sensitivity compared with their wild-type floxed (fl/fl) littermates during hyperinsulinemic euglycemic clamps. Insulin failed to suppress endogenous glucose production in LKO mice, indicating liver insulin resistance. Insulin promoted glucose disappearance in LKO and fl/fl mice similarly. In the liver, insulin failed to induce phosphorylation of Akt-Ser(473) and exclude FOXO1 from the nucleus in LKO mice, a pathway important for liver glucose and lipid metabolism. Liver triglycerides and diacylglycerides were also increased in LKO mice, which corresponded with dysregulation of insulin-stimulated ACC phosphorylation and DGAT1/2 protein levels. Our studies demonstrate that estrogen signaling through ERα in the liver helps prevent whole body and hepatic insulin resistance associated with HFD feeding in males. Augmenting hepatic estrogen signaling through ERα may lessen the impact of obesity on diabetes and cardiovascular risk in males.

  View details for DOI 10.1152/ajpendo.00579.2013

  View details for PubMedID 24691030

  View details for PubMedCentralID PMC4116406

• MicroRNA-223 coordinates cholesterol homeostasis. Proceedings of the National Academy of Sciences of the United States of America Vickers, K. C., Landstreet, S. R., Levin, M. G., Shoucri, B. M., Toth, C. L., Taylor, R. C., Palmisano, B. T., Tabet, F. n., Cui, H. L., Rye, K. A., Sethupathy, P. n., Remaley, A. T. 2014; 111 (40): 14518–23

  Abstract

  MicroRNAs (miRNAs) regulate a wide variety of biological processes and contribute to metabolic homeostasis. Here, we demonstrate that microRNA-223 (miR-223), an miRNA previously associated with inflammation, also controls multiple mechanisms associated with cholesterol metabolism. miR-223 promoter activity and mature levels were found to be linked to cellular cholesterol states in hepatoma cells. Moreover, hypercholesterolemia was associated with increased hepatic miR-223 levels in athero-prone mice. miR-223 was found to regulate high-density lipoprotein-cholesterol (HDL-C) uptake, through direct targeting and repression of scavenger receptor BI, and to inhibit cholesterol biosynthesis through the direct repression of sterol enzymes 3-hydroxy-3-methylglutaryl-CoA synthase 1 and methylsterol monooxygenase 1 in humans. Additionally, miR-223 was found to indirectly promote ATP-binding cassette transporter A1 expression (mRNA and protein) through Sp3, thereby enhancing cellular cholesterol efflux. Finally, genetic ablation of miR-223 in mice resulted in increased HDL-C levels and particle size, as well as increased hepatic and plasma total cholesterol levels. In summary, we identified a critical role for miR-223 in systemic cholesterol regulation by coordinated posttranscriptional control of multiple genes in lipoprotein and cholesterol metabolism.

  View details for DOI 10.1073/pnas.1215767111

  View details for PubMedID 25246565

  View details for PubMedCentralID PMC4210029

• Cholesteryl ester transfer protein protects against insulin resistance in obese female mice. Molecular metabolism Cappel, D. A., Palmisano, B. T., Emfinger, C. H., Martinez, M. N., McGuinness, O. P., Stafford, J. M. 2013; 2 (4): 457–67

  Abstract

  Cholesteryl ester transfer protein (CETP) shuttles lipids between lipoproteins, culminating in cholesteryl ester delivery to liver and increased secretion of cholesterol as bile. Since gut bile acids promote insulin sensitivity, we aimed to define if CETP improves insulin sensitivity with high-fat feeding. CETP and nontransgenic mice of both sexes became obese. Female but not male CETP mice had increased ileal bile acid levels versus nontransgenic littermates. CETP expression protected female mice from insulin resistance but had a minimal effect in males. In liver, female CETP mice showed activation of bile acid-sensitive pathways including Erk1/2 phosphorylation and Fxr and Shp gene expression. In muscle, CETP females showed increased glycolysis, increased mRNA for Dio2, and increased Akt phosphorylation, known effects of bile acid signaling. These results suggest that CETP can ameliorate insulin resistance associated with obesity in female mice, an effect that correlates with increased gut bile acids and known bile-signaling pathways.

  View details for DOI 10.1016/j.molmet.2013.08.007

  View details for PubMedID 24327961

  View details for PubMedCentralID PMC3854988

• Familial evaluation for diagnosis of arrhythmogenic right ventricular dysplasia. Cardiology Palmisano, B. T., Rottman, J. N., Wells, Q. S., DiSalvo, T. G., Hong, C. C. 2011; 119 (1): 47–53

  Abstract

  Most sudden cardiac deaths in young athletes are caused by previously undetected inherited cardiac diseases. Here, we report a case of a young male athlete in whom a presumptive diagnosis of hypertrophic cardiomyopathy (HCM) was made following a near sudden cardiac death. Although his imaging studies initially suggested HCM, a detailed clinical and genetic evaluation of the patient and his asymptomatic father led to the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) in both. DNA sequencing revealed that each individual was heterozygous for two rare variants in the PKP2 and DSC2 genes, both of which were previously shown to be associated with ARVD and to encode desmosomal proteins, i.e. the previously reported splicing variant c2489 + 1A > G in the PKP2 gene and the novel p.I109M variant in the DSC2 gene. Imaging and electrophysiologic studies further supported a diagnosis of ARVD in the father. This case highlights the importance of detailed clinical evaluation and genetic testing of family members when dealing with sudden cardiac death or unexplained cardiomyopathies in the young.

  View details for DOI 10.1159/000329834

  View details for PubMedID 21822014

  View details for PubMedCentralID PMC3169361

• MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nature cell biology Vickers, K. C., Palmisano, B. T., Shoucri, B. M., Shamburek, R. D., Remaley, A. T. 2011; 13 (4): 423–33

  Abstract

  Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. Reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of messenger RNA reporters. Furthermore, HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be dependent on scavenger receptor class B type I. The human HDL-miRNA profile of normal subjects is significantly different from that of familial hypercholesterolemia subjects. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations indicate that HDL participates in a mechanism of intercellular communication involving the transport and delivery of miRNAs.

  View details for DOI 10.1038/ncb2210

  View details for PubMedID 21423178

  View details for PubMedCentralID PMC3074610

• The role of noncoding "junk DNA" in cardiovascular disease. Clinical chemistry Vickers, K. C., Palmisano, B. T., Remaley, A. T. 2010; 56 (10): 1518–20

  View details for DOI 10.1373/clinchem.2010.147603

  View details for PubMedID 20639473