Louis Searcy - Academia.edu (original) (raw)

Papers by Louis Searcy

Abstract 282: A Drosophila Model of Cardiac Lipotoxicity

Circulation Research, 2017

Obesity is associated with cardiovascular disease in humans and a number of model organisms, incl... more Obesity is associated with cardiovascular disease in humans and a number of model organisms, including the fruit fly Drosophila melanogaster . We use a fly model of high-sugar-diet-induced metabolic disease that includes hyperglycemia, insulin resistance, obesity, cardiovascular disease, and reduced longevity. High-sugar-fed flies accumulate lipids in a variety of organs, including the heart. We are using tissue-specific metabolomics and loss-of-function genetics to probe the roles of individual organs and lipids in cardiovascular disease. Our goal is to focus on conserved pathways to better understand how overnutrition with high-calorie diets leads to adverse outcomes in patients with complications of type 2 diabetes.

Journal of Lipid Research, 2020

Diets high in calories can be used to model metabolic diseases, including obesity and its associa... more Diets high in calories can be used to model metabolic diseases, including obesity and its associated comorbidities, in animals. Drosophila melanogaster fed high-sugar diets (HSDs) exhibit complications of human obesity including hyperglycemia, hyperlipidemia, insulin resistance, cardiomyopathy, increased susceptibility to infection, and reduced longevity. We hypothesize that lipid storage in the high-sugar-fed fly’s fat body (FB) reaches a maximum capacity, resulting in the accumulation of toxic lipids in other tissues or lipotoxicity. We took two approaches to characterize tissue-specific lipotoxicity. Ultra-HPLC-MS/MS and MALDI-MS imaging enabled spatial and temporal localization of lipid species in the FB, heart, and hemolymph. Substituent chain length was diet dependent, with fewer odd chain esterified FAs on HSDs in all sample types. By contrast, dietary effects on double bond content differed among organs, consistent with a model where some substituent pools are shared and oth...

MALDI Mass Spectrometric Imaging of the Nematode Caenorhabditis elegans

Current Metabolomics, 2015

ObjectiveAn appreciation of factors that lead to tubular injury in lupus nephritis is lacking. Ir... more ObjectiveAn appreciation of factors that lead to tubular injury in lupus nephritis is lacking. Iron accumulates in the kidney tubules of nephritic patients and lupus-prone nephritic mice. Ferroptosis is a druggable, iron-dependent form of cell death that has received little attention in lupus nephritis. This study investigated whether intra-renal ferroptosis is a target for intervention in lupus nephritis.MethodsKidneys of lupus nephritis patients and two spontaneous murine models of lupus nephritis were characterized for ferroptosis using protein, RNA, and lipidomics-based approaches. Susceptibility of heavy chain ferritin (FtH1; an essential iron sequestration protein) deficient proximal tubular epithelial cells (PTECs) was studied using nephrotoxic serum nephritis and FtH1 knockdown human PTECs. The benefit of Liproxstatin-2, a novel second-generation ferroptosis, was evaluated using human PTECs exposed to lupus nephritis patients’ serum.ResultsHuman and murine nephritic kidneys ...

Abstract 282: A Drosophila Model of Cardiac Lipotoxicity

Circulation Research, 2017

Obesity is associated with cardiovascular disease in humans and a number of model organisms, incl... more Obesity is associated with cardiovascular disease in humans and a number of model organisms, including the fruit fly Drosophila melanogaster . We use a fly model of high-sugar-diet-induced metabolic disease that includes hyperglycemia, insulin resistance, obesity, cardiovascular disease, and reduced longevity. High-sugar-fed flies accumulate lipids in a variety of organs, including the heart. We are using tissue-specific metabolomics and loss-of-function genetics to probe the roles of individual organs and lipids in cardiovascular disease. Our goal is to focus on conserved pathways to better understand how overnutrition with high-calorie diets leads to adverse outcomes in patients with complications of type 2 diabetes.

Journal of Lipid Research, 2020

Diets high in calories can be used to model metabolic diseases, including obesity and its associa... more Diets high in calories can be used to model metabolic diseases, including obesity and its associated comorbidities, in animals. Drosophila melanogaster fed high-sugar diets (HSDs) exhibit complications of human obesity including hyperglycemia, hyperlipidemia, insulin resistance, cardiomyopathy, increased susceptibility to infection, and reduced longevity. We hypothesize that lipid storage in the high-sugar-fed fly’s fat body (FB) reaches a maximum capacity, resulting in the accumulation of toxic lipids in other tissues or lipotoxicity. We took two approaches to characterize tissue-specific lipotoxicity. Ultra-HPLC-MS/MS and MALDI-MS imaging enabled spatial and temporal localization of lipid species in the FB, heart, and hemolymph. Substituent chain length was diet dependent, with fewer odd chain esterified FAs on HSDs in all sample types. By contrast, dietary effects on double bond content differed among organs, consistent with a model where some substituent pools are shared and oth...

MALDI Mass Spectrometric Imaging of the Nematode Caenorhabditis elegans

Current Metabolomics, 2015

ObjectiveAn appreciation of factors that lead to tubular injury in lupus nephritis is lacking. Ir... more ObjectiveAn appreciation of factors that lead to tubular injury in lupus nephritis is lacking. Iron accumulates in the kidney tubules of nephritic patients and lupus-prone nephritic mice. Ferroptosis is a druggable, iron-dependent form of cell death that has received little attention in lupus nephritis. This study investigated whether intra-renal ferroptosis is a target for intervention in lupus nephritis.MethodsKidneys of lupus nephritis patients and two spontaneous murine models of lupus nephritis were characterized for ferroptosis using protein, RNA, and lipidomics-based approaches. Susceptibility of heavy chain ferritin (FtH1; an essential iron sequestration protein) deficient proximal tubular epithelial cells (PTECs) was studied using nephrotoxic serum nephritis and FtH1 knockdown human PTECs. The benefit of Liproxstatin-2, a novel second-generation ferroptosis, was evaluated using human PTECs exposed to lupus nephritis patients’ serum.ResultsHuman and murine nephritic kidneys ...