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Article ; Online: Nitrated fatty acids: from diet to disease.

Khoo, Nicholas K H / Schopfer, Francisco J

2019 Volume 9, Page(s) 67–72

Abstract: Fatty acids not only provide caloric energy in our diets and building blocks of lipids but are also precursors of potent signaling molecules. Fatty acids can undergo enzymatic and non-enzymatic transformations to form autocrine and paracrine signaling ... ...

Abstract	Fatty acids not only provide caloric energy in our diets and building blocks of lipids but are also precursors of potent signaling molecules. Fatty acids can undergo enzymatic and non-enzymatic transformations to form autocrine and paracrine signaling molecules that regulate energy balance and metabolic homeostasis. A new class of lipid signaling mediators known as nitro-fatty acids (NO
Language	English
Publishing date	2019-04-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2918626-2
ISSN	2468-8673 ; 2468-8681
ISSN (online)	2468-8673
ISSN	2468-8681
DOI	10.1016/j.cophys.2019.04.013
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Article ; Online: Nitro-Fatty Acid Logistics: Formation, Biodistribution, Signaling, and Pharmacology.

Schopfer, Francisco J / Khoo, Nicholas K H

Trends in endocrinology and metabolism: TEM

2019 Volume 30, Issue 8, Page(s) 505–519

Abstract: In addition to supporting cellular energetic demands and providing building blocks for lipid synthesis, fatty acids (FAs) are precursors of potent signaling molecules. In particular, the presence of conjugated double bonds on the fatty-acyl chain ... ...

Abstract	In addition to supporting cellular energetic demands and providing building blocks for lipid synthesis, fatty acids (FAs) are precursors of potent signaling molecules. In particular, the presence of conjugated double bonds on the fatty-acyl chain provides a preferential target for nitration generating nitro-FAs (NO
MeSH term(s)	Animals ; Fatty Acids/metabolism ; Humans ; Inflammation/metabolism ; Nitro Compounds/metabolism ; Nitrogen Dioxide/metabolism ; Signal Transduction/physiology
Chemical Substances	Fatty Acids ; Nitro Compounds ; Nitrogen Dioxide (S7G510RUBH)
Language	English
Publishing date	2019-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1042384-9
ISSN	1879-3061 ; 1043-2760
ISSN (online)	1879-3061
ISSN	1043-2760
DOI	10.1016/j.tem.2019.04.009
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Zs.A 2999: Show issues

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Article ; Online: Inflammatory signaling and metabolic regulation by nitro-fatty acids.

Rom, Oren / Khoo, Nicholas K H / Chen, Y Eugene / Villacorta, Luis

Nitric oxide : biology and chemistry

2018

Abstract: The addition of nitrogen dioxide ( ... ...

Abstract	The addition of nitrogen dioxide (NO
Language	English
Publishing date	2018-03-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1362794-6
ISSN	1089-8611 ; 1089-8603
ISSN (online)	1089-8611
ISSN	1089-8603
DOI	10.1016/j.niox.2018.03.017
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Zs.A 4677: Show issues

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Article ; Online: Obese female mice do not exhibit overt hyperuricemia despite hepatic steatosis and impaired glucose tolerance.

Lewis, Sara E / Li, Lihua / Fazzari, Marco / Salvatore, Sonia R / Li, Jiang / Hileman, Emily A / Maxwell, Brooke A / Schopfer, Francisco J / Arteel, Gavin E / Khoo, Nicholas K H / Kelley, Eric E

Advances in redox research : an official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe

2022 Volume 6

Abstract: Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a ... ...

Abstract	Recent reports have clearly demonstrated a tight correlation between obesity and elevated circulating uric acid levels (hyperuricemia). However, nearly all preclinical work in this area has been completed with male mice, leaving the field with a considerable gap in knowledge regarding female responses to obesity and hyperuricemia. This deficiency in sex as a biological variable extends beyond unknowns regarding uric acid (UA) to several important comorbidities associated with obesity including nonalcoholic fatty liver disease (NAFLD). To attempt to address this issue, herein we describe both phenotypic and metabolic responses to diet-induced obesity (DIO) in female mice. Six-week-old female C57BL/6J mice were fed a high-fat diet (60% calories derived from fat) for 32 weeks. The DIO female mice had significant weight gain over the course of the study, higher fasting blood glucose, impaired glucose tolerance, and elevated plasma insulin levels compared to age-matched on normal chow. While these classic indices of DIO and NAFLD were observed such as increased circulating levels of ALT and AST, there was no difference in circulating UA levels. Obese female mice also demonstrated increased hepatic triglyceride (TG), cholesterol, and cholesteryl ester. In addition, several markers of hepatic inflammation were significantly increased. Also, alterations in the expression of redox-related enzymes were observed in obese mice compared to lean controls including increases in extracellular superoxide dismutase (Sod3), heme oxygenase (Ho)-1, and xanthine dehydrogenase (Xdh). Interestingly, hepatic UA levels were significantly elevated (~2-fold) in obese mice compared to their lean counterparts. These data demonstrate female mice assume a similar metabolic profile to that reported in several male models of obesity in the context of alterations in glucose tolerance, hepatic steatosis, and elevated transaminases (ALT and AST) in the absence of hyperuricemia affirming the need for further study.
Language	English
Publishing date	2022-10-07
Publishing country	Netherlands
Document type	Journal Article
ISSN	2667-1379
ISSN (online)	2667-1379
DOI	10.1016/j.arres.2022.100051
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Article ; Online: Nitro-oleic acid and epoxyoleic acid are not altered in obesity and type 2 diabetes: reply.

Schopfer, Francisco J / Freeman, Bruce A / Khoo, Nicholas K H

Cardiovascular research

2014 Volume 102, Issue 3, Page(s) 518

MeSH term(s)	Female ; Gas Chromatography-Mass Spectrometry/methods ; Humans ; Male ; Nitrogen Isotopes/chemistry ; Oleic Acids/chemistry ; Tandem Mass Spectrometry/methods
Chemical Substances	Nitrogen Isotopes ; Oleic Acids
Language	English
Publishing date	2014-02-21
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	80340-6
ISSN	1755-3245 ; 0008-6363
ISSN (online)	1755-3245
ISSN	0008-6363
DOI	10.1093/cvr/cvu042
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Zs.A 565: Show issues

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Article ; Online: Electrophilic fatty acid nitroalkenes regulate Nrf2 and NF-κB signaling:A medicinal chemistry investigation of structure-function relationships.

Khoo, Nicholas K H / Li, Lihua / Salvatore, Sonia R / Schopfer, Francisco J / Freeman, Bruce A

Scientific reports

2018 Volume 8, Issue 1, Page(s) 2295

Abstract: Fatty acid nitroalkene derivatives ( ... ...

Abstract	Fatty acid nitroalkene derivatives (NO
MeSH term(s)	Alkenes/chemical synthesis ; Alkenes/chemistry ; Alkenes/metabolism ; Animals ; Chemical Phenomena ; Fatty Acids/chemical synthesis ; Fatty Acids/chemistry ; Fatty Acids/metabolism ; Genes, Reporter ; Luciferases/analysis ; Luciferases/genetics ; Macrophages/drug effects ; Mice ; Molecular Structure ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/metabolism ; Nitro Compounds/chemical synthesis ; Nitro Compounds/chemistry ; Nitro Compounds/metabolism ; RAW 264.7 Cells ; Signal Transduction/drug effects
Chemical Substances	Alkenes ; Fatty Acids ; NF-E2-Related Factor 2 ; NF-kappa B ; NFE2L2 protein, human ; Nitro Compounds ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2018-02-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-20460-8
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Article ; Online: The global syndemic of metabolic diseases in the young adult population: A consortium of trends and projections from the Global Burden of Disease 2000-2019.

Chong, Bryan / Kong, Gwyneth / Shankar, Kannan / Chew, H S Jocelyn / Lin, Chaoxing / Goh, Rachel / Chin, Yip Han / Tan, Darren Jun Hao / Chan, Kai En / Lim, Wen Hui / Syn, Nicholas / Chan, Siew Pang / Wang, Jiong-Wei / Khoo, Chin Meng / Dimitriadis, Georgios K / Wijarnpreecha, Karn / Sanyal, Arun / Noureddin, Mazen / Siddiqui, Mohammad Shadab /

Foo, Roger / Mehta, Anurag / Figtree, Gemma A / Hausenloy, Derek J / Chan, Mark Y / Ng, Cheng Han / Muthiah, Mark / Mamas, Mamas A / Chew, Nicholas W S

Metabolism: clinical and experimental

2023 Volume 141, Page(s) 155402

Abstract: Background: A significant proportion of premature deaths globally are related to metabolic diseases in young adults. We examined the global trends and mortality of metabolic diseases in individuals aged below 40 years using data from the Global Burden ... ...

Abstract	Background: A significant proportion of premature deaths globally are related to metabolic diseases in young adults. We examined the global trends and mortality of metabolic diseases in individuals aged below 40 years using data from the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019. Methods: From 2000 to 2019, global estimates of deaths and disability-adjusted life years (DALYs) were described for metabolic diseases (type 2 diabetes mellitus [T2DM], hyperlipidemia, hypertension, obesity, non-alcoholic fatty liver disease [NAFLD]). Subgroup analyses were performed based on sex, geographical regions and Socio-Demographic Index (SDI). Age-standardised death and DALYs were presented per 100,000 population with 95 % uncertainty intervals (UI). Projections of mortality and DALYs were estimated using regression models based on the GBD 2019 data and combining them with Institute for Health Metrics and Evaluation projection counts for years up to 2050. Results: In 2019, the highest age-standardised death rates were observed in hypertension (133·88 [121·25-155·73]), followed by obesity (62·59 [39·92-89·13]), hyperlipidemia (56·51 [41·83-73·62]), T2DM (18·49 [17·18-19·66]) and NAFLD (2·09 [1·61-2·60]). Similarly, obesity (1932·54 [1276·61-2639·74]) had the highest age-standardised DALYs, followed by hypertension (2885·57 [2580·75-3201·05]), hyperlipidemia (1207·15 [975·07-1461·11]), T2DM (801·55 [670·58-954·43]) and NAFLD (53·33 [40·73-68·29]). Mortality rates decreased over time in hyperlipidemia (-0·6 %), hypertension (-0·47 %), NAFLD (-0·31 %) and T2DM (-0·20 %), but not in obesity (1·07 % increase). The highest metabolic-related mortality was observed in Eastern Mediterranean and low SDI countries. By 2050, obesity is projected to contribute to the largest number of deaths (102·8 % increase from 2019), followed by hypertension (61·4 % increase), hyperlipidemia (60·8 % increase), T2DM (158·6 % increase) and NAFLD (158·4 % increase), with males continuing to bear the greatest burden across all metabolic diseases. Conclusion: The growing burden of metabolic diseases, increasing obesity-related mortality trends, and the sex-regional-socioeconomic disparities evident in young adulthood, underlie the concerning growing global burden of metabolic diseases now and in future.
MeSH term(s)	Male ; Humans ; Young Adult ; Adult ; Aged ; Global Burden of Disease ; Quality-Adjusted Life Years ; Non-alcoholic Fatty Liver Disease ; Diabetes Mellitus, Type 2 ; Syndemic ; Risk Factors ; Metabolic Diseases ; Obesity ; Hypertension
Language	English
Publishing date	2023-01-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80230-x
ISSN	1532-8600 ; 0026-0495
ISSN (online)	1532-8600
ISSN	0026-0495
DOI	10.1016/j.metabol.2023.155402
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Article ; Online: A two-decade population-based study on the effect of hypertension in the general population with obesity in the United States.

Obesity (Silver Spring, Md.)

2023 Volume 31, Issue 3, Page(s) 832–840

Abstract: Objective: With rising prevalence of hypertension and obesity, the effect of hypertension in obesity remains an important global issue. The prognosis of the US general population with obesity based on hypertension control was examined.: Methods: This ...

Abstract	Objective: With rising prevalence of hypertension and obesity, the effect of hypertension in obesity remains an important global issue. The prognosis of the US general population with obesity based on hypertension control was examined. Methods: This study examined participants from the National Health and Nutrition Examination Survey between 1999 and 2018. Individuals with obesity were stratified into no hypertension, controlled hypertension, and uncontrolled hypertension. The study outcome was all-cause mortality. Cox regression of all-cause mortality was adjusted for age, sex, ethnicity, diabetes, and previous myocardial infarction. Results: Of 16,386 individuals with obesity, 53.1% had no hypertension, 24.7% had controlled hypertension, and 22.2% had uncontrolled hypertension. All-cause mortality was significantly higher in uncontrolled hypertension (17.1%), followed by controlled hypertension (14.8%) and no hypertension (4.0%). Uncontrolled hypertension had the highest mortality risk (hazard ratio [HR] 1.34, 95% CI: 1.13-1.59, p = 0.001), followed by controlled hypertension (HR 1.21, 95% CI: 1.10-1.34, p < 0.001), compared with no hypertension after adjustment. The excess mortality trend was more pronounced in females, those with diabetes, and those older than age 65 years. Conclusions: The incremental mortality risk in controlled and uncontrolled hypertension, compared with the normotensive counterparts, irrespective of sex, age, and diabetes status, urges health care providers to optimize hypertension control and advocate weight loss to achieve better outcomes in obesity.
MeSH term(s)	Female ; Humans ; United States ; Aged ; Nutrition Surveys ; Hypertension/epidemiology ; Obesity/epidemiology ; Diabetes Mellitus ; Blood Pressure ; Risk Factors
Language	English
Publishing date	2023-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1002/oby.23658
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Article ; Online: Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis.

Khoo, Nicholas K H / Fazzari, Marco / Chartoumpekis, Dionysios V / Li, Lihua / Guimaraes, Danielle Aparecida / Arteel, Gavin E / Shiva, Sruti / Freeman, Bruce A

Redox biology

2019 Volume 22, Page(s) 101132

Abstract: Non-alcoholic fatty liver disease (NAFLD) is linked to obesity and insulin resistance and is the most prevalent chronic liver disease. During the development of obesity and NAFLD, mitochondria adapt to the increased lipid load in hepatocytes by ... ...

Abstract	Non-alcoholic fatty liver disease (NAFLD) is linked to obesity and insulin resistance and is the most prevalent chronic liver disease. During the development of obesity and NAFLD, mitochondria adapt to the increased lipid load in hepatocytes by increasing the rate of fatty acid oxidation. In concert with this, reactive species (RS) generation is increased, damaging hepatocytes and inducing inflammation. Hepatic mitochondrial dysfunction is central to the pathogenesis of NAFLD via undefined mechanisms. There are no FDA approved treatments for NAFLD other than weight loss and management of glucose tolerance. Electrophilic nitro-oleic acid (NO
MeSH term(s)	Adipose Tissue/drug effects ; Adipose Tissue/metabolism ; Animals ; Biomarkers ; Blood Glucose ; Body Weight/drug effects ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Glucose Intolerance ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Lipid Metabolism ; Male ; Mice ; Mitochondria, Liver/drug effects ; Mitochondria, Liver/metabolism ; Non-alcoholic Fatty Liver Disease/drug therapy ; Non-alcoholic Fatty Liver Disease/etiology ; Non-alcoholic Fatty Liver Disease/pathology ; Obesity/complications ; Obesity/metabolism ; Oleic Acids/chemistry ; Oleic Acids/pharmacology ; Protective Agents/chemistry ; Protective Agents/pharmacology ; Rosiglitazone/pharmacology ; Triglycerides/metabolism
Chemical Substances	Biomarkers ; Blood Glucose ; Oleic Acids ; Protective Agents ; Triglycerides ; Rosiglitazone (05V02F2KDG)
Language	English
Publishing date	2019-02-01
Publishing country	Netherlands
Document type	Journal Article
ISSN	2213-2317
ISSN (online)	2213-2317
DOI	10.1016/j.redox.2019.101132
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Article ; Online: Immunomodulatory actions of a kynurenine-derived endogenous electrophile.

Carreño, Mara / Pires, Maria F / Woodcock, Steven R / Brzoska, Tomasz / Ghosh, Samit / Salvatore, Sonia R / Chang, Fei / Khoo, Nicholas K H / Dunn, Matthew / Connors, Nora / Yuan, Shuai / Straub, Adam C / Wendell, Stacy G / Kato, Gregory J / Freeman, Bruce A / Ofori-Acquah, Solomon F / Sundd, Prithu / Schopfer, Francisco J / Vitturi, Dario A

Science advances

2022 Volume 8, Issue 26, Page(s) eabm9138

Abstract: The up-regulation of kynurenine metabolism induces immunomodulatory responses via incompletely understood mechanisms. We report that increases in cellular and systemic kynurenine levels yield the electrophilic derivative kynurenine-carboxyketoalkene (Kyn- ...

Abstract	The up-regulation of kynurenine metabolism induces immunomodulatory responses via incompletely understood mechanisms. We report that increases in cellular and systemic kynurenine levels yield the electrophilic derivative kynurenine-carboxyketoalkene (Kyn-CKA), as evidenced by the accumulation of thiol conjugates and saturated metabolites. Kyn-CKA induces NFE2 like bZIP transcription factor 2- and aryl hydrocarbon receptor-regulated genes and inhibits nuclear factor κB- and NLR family pyrin domain containing 3-dependent proinflammatory signaling. Sickle cell disease (SCD) is a hereditary hemolytic condition characterized by basal inflammation and recurrent vaso-occlusive crises. Both transgenic SCD mice and patients with SCD exhibit increased kynurenine and Kyn-CKA metabolite levels. Plasma hemin and kynurenine concentrations are positively correlated, indicating that Kyn-CKA synthesis in SCD is up-regulated during pathogenic vascular stress. Administration of Kyn-CKA abrogated pulmonary microvasculature occlusion in SCD mice, an important factor in lung injury development. These findings demonstrate that the up-regulation of kynurenine synthesis and its metabolism to Kyn-CKA is an adaptive response that attenuates inflammation and protects tissues.
Language	English
Publishing date	2022-06-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abm9138
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