Caroline Tao

Amgen (United States)

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Philipp E. Scherer

The University of Texas Southwestern Medical Center

Qiong Wang

Central South University of Forestry and Technology

Rana K. Gupta

Duke University

Mengle Shao

Chinese Academy of Sciences

William L. Holland

University of Utah

Risheng Ye

University of Science and Technology of China

Joel K. Elmquist

The University of Texas Southwestern Medical Center

Ingrid Wernstedt Asterholm

University of Gothenburg

Lei Jiang

Chinese Academy of Agricultural Sciences

Kai Sun

Nanjing Medical University

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Matrix Research (United States)

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The University of Texas Southwestern Medical Center

Southwestern Medical Center

Centre National de la Recherche Scientifique

Harvard University

University of California, Los Angeles

Johns Hopkins University

The University of Texas Health Science Center at San Antonio

Amgen (United States)

The University of Texas Health Science Center at Houston

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Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice

Scientific Reports (2021)

Hongfei Ge Gongxin Liu Tracy M. Yamawaki Caroline Tao Shawn T. Alexander

Abstract Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.

Phytosterol

Cardiac Fibrosis

Sudden Death

Cardiac arrhythmia

Pathogenesis

10.1038/s41598-021-96936-x

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Citations (3)

Subchondral Fractures in Osteonecrosis of the Femoral Head: Comparison of Radiography, CT, and MR Imaging

American Journal of Roentgenology (2003)

Kathryn J. Stevens Caroline Tao Shi-Uk Lee Natalie Salem Jan Vandevenne

Our objective was to compare the sensitivity of unenhanced radiography, CT, and MR imaging in revealing subchondral fractures.Forty-five subjects with stage I and stage II osteonecrosis of the femoral head were included in the study as part of a multicenter clinical trial to evaluate the effectiveness of recombinant human bone morphogenetic protein as an adjuvant treatment to core decompression. Patients were evaluated with radiography, CT, and MR imaging 6 and 12 months after surgery.At 6 months, 18 fractures were shown on CT scans, but only 12 were detected on radiographs and six, on MR images. At 12 months, 20 subchondral fractures were detected on CT scans, but only 17 were seen on radiographs and 11, on MR images. Compared with CT, MR imaging has a sensitivity and specificity of 38% and 100%, and unenhanced radiography has a sensitivity and specificity of 71% and 97%, respectively. On T2-weighted MR images, the subchondral fractures were visualized as crescentic high-signal-intensity lines, and in all patients, on the corresponding CT scans, the fracture clearly breached the femoral cortex.CT reveals more subchondral fractures in osteonecrosis of the femoral head than unenhanced radiography or MR imaging. The high-signal-intensity line seen on T2-weighted MR images appears to represent fluid accumulating in the subchondral fracture, which may indicate a breach in the overlying articular cartilage.

Conventional radiography

10.2214/ajr.180.2.1800363

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Citations (138)

Short-Term Versus Long-Term Effects of Adipocyte Toll-Like Receptor 4 Activation on Insulin Resistance in Male Mice

Endocrinology (2017)

Caroline Tao William L. Holland Qiong Wang Mengle Shao Lin Jia

Chronic exposure to high–saturated fat diets (HFDs) increases the prevalence of obesity and contributes to the development of low-grade inflammation and insulin resistance. A possible mediator accounting for obesity-associated inflammation and insulin resistance is Toll-like receptor 4 (TLR4). We investigated the role of adipocyte TLR4 in lipid and glucose homeostasis through an inducible, adipocyte-specific deletion of TLR4 in a mouse model that is referred to as the "Tadipo" mouse. Consistent with a critical role for inflammation as a positive force for healthy adipose tissue expansion, chronic HFD exposure results in exacerbated whole-body and muscle insulin resistance in the absence of TLR4 in the adipocyte. Elimination of TLR4 in adipocytes affects TLR4 expression in other tissues, with reduced TLR4 expression in peritoneal macrophages and in the liver. In contrast, TLR4 deletion from adipocytes protects whole-body insulin sensitivity after an acute lipid challenge during a hyperinsulinemic euglycemic clamp. Our results therefore demonstrate dichotomous effects of TLR4 on adipose tissue functionality, with an important positive role of TLR4 during a chronic HFD challenge due to the lack of adipose tissue remodeling and a negative role of TLR4 as a mediator of insulin resistance in the adipocyte during an acute challenge with saturated fatty acids.

10.1210/en.2017-00024

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Citations (36)

A NovelADIPOQMutation (p.M40K) Impairs Assembly of High-Molecular-Weight Adiponectin and Is Associated With Early-Onset Obesity and Metabolic Syndrome

The Journal of Clinical Endocrinology & Metabolism (2014)

Ana Carolina Bueno Kai Sun Clarissa Silva Martins Jorge Elías Wallace Rodrigues de Holanda Miranda

The phenotypic effects of ADIPOQ mutations early in life, prior to type 2 diabetes onset, have not been studied.The objective of the study was to characterize the impact of a novel ADIPOQ mutation in vitro and in vivo.The design of the study was ADIPOQ screening, adiponectin oligomerization, and cardiometabolic phenotype assessment.Fourteen hypoadiponectinemic (<3 μg/mL) and 686 normoadiponectinemic young adults (23-25 y) were prospectively followed up since birth.Human and recombinant murine mutant adiponectin oligomerization, the proband's ADIPOQ and ADIPOR1/R2 adipose tissue (AT) expression, and cardiometabolic profile were measured.The heterozygous ADIPOQ p.M40K mutation was identified in one hypoadiponectinemic male (2.4 μg/mL) and three other family members. Carriers presented a marked reduction of serum high-molecular weight to total adiponectin ratio when compared with controls (9.4% ± 1% vs 56.6% ± 13%; P < .05) and family noncarriers (9.4% ± 1% vs 42% ± 0.5%; P = .05). Both mRNA and protein levels of adiponectin were increased in the AT of the proband (2.3- and 1.6-fold, respectively). However, the high-molecular weight to total adiponectin ratio of adiponectin was decreased (3.3-fold). Moreover, the expressions of ADIPOR1 and ADIPOR2 were significantly down-regulated in the AT of the proband (6- and 1.2-fold, respectively). The results were confirmed by in vitro studies on the recombinant murine homologous mutation (p.M43K). The proband's cardiometabolic phenotype progression was further characterized: born small for gestational age and adolescence-onset obesity; insulin resistance (homeostasis assessment model of insulin resistance of 4.7), and dyslipidemia at 25 years; decreased high-molecular weight adiponectin (0.24 μg/mL = 10%), hypertension (180/120 mm Hg), steatosis (fat liver = 40% ± 6%), increased carotid intima-media thickness at 31 years, and type 2 diabetes (glycosylated hemoglobin = 6.6%) at 34 years of age. Of note, all of the affected family members presented features of metabolic syndrome.The newly identified ADIPOQ p.M40K mutation associates with severe cardiometabolic dysfunction due to the impairment of high-molecular weight adiponectin complex formation.

Proband

10.1210/jc.2013-3009

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Citations (24)

Regulation of glucose and lipid homeostasis by adiponectin: Effects on hepatocytes, pancreatic β cells and adipocytes

Best Practice & Research Clinical Endocrinology & Metabolism (2013)

Caroline Tao Angelica J. Sifuentes William L. Holland

Lipotoxicity

Sphingolipid

10.1016/j.beem.2013.11.003

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Citations (115)

B-PO03-089 APPLICATION OF DYNAMIC MAPPING DATA IN POSTERIOR WALL ISOLATION DURING RADIOFREQUENCY CATHETER ABLATION OF ATRIAL FIBRILLATION

Heart Rhythm (2021)

Hemanth Ramanna Arian Sultan James McCready Michael L. Bernard Koichiro Kumagai

10.1016/j.hrthm.2021.06.563

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Pathological Type-2 Immune Response, Enhanced Tumor Growth, and Glucose Intolerance in Retnlβ (RELMβ) Null Mice

American Journal Of Pathology (2016)

Ingrid Wernstedt Asterholm Ja Young Kim-Muller Joseph M. Rutkowski Clair Crewe Caroline Tao

Resistin

Pathogenesis

Homeostasis

10.1016/j.ajpath.2016.04.017

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Citations (10)

Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

Nature Communications (2014)

Lin Jia Cláudia R. Vianna Makoto Fukuda Eric D. Berglund Chen Liu

Steatosis

10.1038/ncomms4878

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Citations (261)

Impact of tamoxifen on adipocyte lineage tracing: Inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase

Molecular Metabolism (2015)

Risheng Ye Qiong Wang Caroline Tao Lavanya Vishvanath Mengle Shao

The selective estrogen receptor modulator tamoxifen, in combination with the Cre-ER(T2) fusion protein, has been one of the mainstream methods to induce genetic recombination and has found widespread application in lineage tracing studies.Here, we report that tamoxifen exposure at widely used concentrations remains detectable by mass-spectrometric analysis in adipose tissue after a washout period of 10 days. Surprisingly, its ability to maintain nuclear translocation of the Cre-ER(T2) protein is preserved beyond 2 months of washout. Tamoxifen treatment acutely leads to transient lipoatrophy, followed by de novo adipogenesis that reconstitutes the original fat mass. In addition, we find a "synthetically lethal" phenotype for adipocytes when tamoxifen treatment is combined with adipocyte-specific loss-of-function mutants, such as an adipocyte-specific PPARγ knockout. This is observed to a lesser extent when alternative inducible approaches are employed.These findings highlight the potential for tamoxifen-induced adipogenesis, and the associated drawbacks of the use of tamoxifen in lineage tracing studies, explaining the discrepancy in lineage tracing results from different systems with temporal control of gene targeting.

Cre recombinase

10.1016/j.molmet.2015.08.004

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Citations (113)

The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

Journal of Clinical Investigation (2012)

Yingfeng Deng Zhao V. Wang Caroline Tao Ningguo Gao William L. Holland

Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation. Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated. Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources. Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s. Using a mouse model with liver-specific inducible Xbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx. Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect. Our results provide evidence that the Xbp1s/GalE pathway functions as a novel regulatory nexus connecting the UPR to the characteristic postprandial metabolic changes in hepatocytes.

Mediator

Carbohydrate-responsive element-binding protein

XBP1

10.1172/jci62819

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Citations (128)