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Article: Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats.

Palfrey, Henry A / Kumar, Avinash / Pathak, Rashmi / Stone, Kirsten P / Gettys, Thomas W / Murthy, Subramanyam N

Research square

2024

Abstract: Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and ... ...

Abstract	Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. Thus, Methods: Six-week-old adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with vehicle (water) or Results: Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin. Conclusion: Adverse cardiac outcomes in HChol were enhanced with sitagliptin administration and such effects were alleviated by Met. Our findings could be significant for understanding the risk-benefit of sitagliptin in type 2 diabetics who are known to consume atherogenic diets.
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-4075353/v1
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Article: Differential responses to maternal diabetes in embryo and visceral yolk sac.

Salbaum, J Michael / Stone, Kirsten P / Kruger, Claudia / Kappen, Claudia

Frontiers in cell and developmental biology

2023 Volume 11, Page(s) 1273641

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-10-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2023.1273641
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Article ; Online: The Origins, Evolution, and Future of Dietary Methionine Restriction.

Fang, Han / Stone, Kirsten P / Wanders, Desiree / Forney, Laura A / Gettys, Thomas W

Annual review of nutrition

2022 Volume 42, Page(s) 201–226

Abstract: The original description of dietary methionine restriction (MR) used semipurified diets to limit methionine intake to 20% of normal levels, and this reduction in dietary methionine increased longevity by ∼30% in rats. The MR diet also produces ... ...

Abstract	The original description of dietary methionine restriction (MR) used semipurified diets to limit methionine intake to 20% of normal levels, and this reduction in dietary methionine increased longevity by ∼30% in rats. The MR diet also produces paradoxical increases in energy intake and expenditure and limits fat deposition while reducing tissue and circulating lipids and enhancing overall insulin sensitivity. In the years following the original 1993 report, a comprehensive effort has been made to understand the nutrient sensing and signaling systems linking reduced dietary methionine to the behavioral, physiological, biochemical, and transcriptional components of the response. Recent work has shown that transcriptional activation of hepatic fibroblast growth factor 21 (FGF21) is a key event linking the MR diet to many but not all components of its metabolic phenotype. These findings raise the interesting possibility of developing therapeutic, MR-based diets that produce the beneficial effects of FGF21 by nutritionally modulating its transcription and release.
MeSH term(s)	Animals ; Diet ; Energy Intake ; Energy Metabolism ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism ; Humans ; Insulin Resistance ; Liver/metabolism ; Methionine/metabolism ; Rats
Chemical Substances	Fibroblast Growth Factors (62031-54-3) ; Methionine (AE28F7PNPL)
Language	English
Publishing date	2022-05-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	406980-8
ISSN	1545-4312 ; 0199-9885
ISSN (online)	1545-4312
ISSN	0199-9885
DOI	10.1146/annurev-nutr-062320-111849
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Article: The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein

Fang, Han / Stone, Kirsten P. / Ghosh, Sujoy / Forney, Laura A. / Gettys, Thomas W.

Nutrients. 2021 July 29, v. 13, no. 8

2021

Abstract: Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e. ...

Abstract	Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.
Keywords	adipose tissue ; body weight ; casein ; cystine ; energy expenditure ; energy intake ; fibroblast growth factors ; methionine ; phenotype ; soy protein ; sulfur ; transcription (genetics)
Language	English
Dates of publication	2021-0729
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13082609
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Article: Nutritional Regulation of Hepatic FGF21 by Dietary Restriction of Methionine.

Fang, Han / Stone, Kirsten P / Forney, Laura A / Wanders, Desiree / Gettys, Thomas W

Frontiers in endocrinology

2021 Volume 12, Page(s) 773975

Abstract: FGF21 is a potent metabolic regulator of energy balance, body composition, lipid metabolism, and glucose homeostasis. Initial studies reported that it was increased by fasting and the associated increase in ketones, but more recent work points to the ... ...

Abstract	FGF21 is a potent metabolic regulator of energy balance, body composition, lipid metabolism, and glucose homeostasis. Initial studies reported that it was increased by fasting and the associated increase in ketones, but more recent work points to the importance of dietary protein and sensing of essential amino acids in FGF21 regulation. For example, dietary restriction of methionine produces a rapid transcriptional activation of hepatic FGF21 that results in a persistent 5- to 10-fold increase in serum FGF21. Although FGF21 is a component of a complex transcriptional program activated by methionine restriction (MR), loss-of-function studies show that FGF21 is an essential mediator of the resulting effects of the MR diet on energy balance, remodeling of adipose tissue, and enhancement of insulin sensitivity. These studies also show that FGF21 signaling in the brain is required for the MR diet-induced increase in energy expenditure (EE) and reduction of adiposity. Collectively, the evidence supports the view that the liver functions as a sentinel to detect and respond to changes in dietary amino acid composition, and that the resulting mobilization of hepatic FGF21 is a key element of the homeostatic response. These findings raise the interesting possibility that therapeutic diets could be developed that produce sustained, biologically effective increases in FGF21 by nutritionally modulating its transcription and release.
MeSH term(s)	Animals ; Diet, Protein-Restricted ; Fibroblast Growth Factors/metabolism ; Humans ; Insulin Resistance/physiology ; Liver/metabolism ; Methionine/metabolism
Chemical Substances	fibroblast growth factor 21 ; Fibroblast Growth Factors (62031-54-3) ; Methionine (AE28F7PNPL)
Language	English
Publishing date	2021-11-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2021.773975
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Article ; Online: The Role of Reduced Methionine in Mediating the Metabolic Responses to Protein Restriction Using Different Sources of Protein.

Fang, Han / Stone, Kirsten P / Ghosh, Sujoy / Forney, Laura A / Gettys, Thomas W

Nutrients

2021 Volume 13, Issue 8

Abstract	Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.
MeSH term(s)	Adipose Tissue/metabolism ; Amino Acids, Essential ; Amino Acids, Sulfur ; Animals ; Body Weight ; Caseins ; Diet, Protein-Restricted ; Eating ; Energy Intake ; Energy Metabolism/physiology ; Fibroblast Growth Factors/metabolism ; Gene Expression ; Humans ; Liver/metabolism ; Male ; Methionine/metabolism ; Methionine/pharmacology ; Mice ; Mice, Inbred C57BL ; Soybean Proteins ; Transcriptome
Chemical Substances	Amino Acids, Essential ; Amino Acids, Sulfur ; Caseins ; Soybean Proteins ; fibroblast growth factor 21 ; Fibroblast Growth Factors (62031-54-3) ; Methionine (AE28F7PNPL)
Language	English
Publishing date	2021-07-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13082609
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Article ; Online: Prolonged effects of DPP-4 inhibitors on steato-hepatitic changes in Sprague-Dawley rats fed a high-cholesterol diet.

Pathak, Rashmi / Kumar, Avinash / Palfrey, Henry A / Stone, Kirsten P / Raju, Narayan R / Gettys, Thomas W / Murthy, Subramanyam N

Inflammation research : official journal of the European Histamine Research Society ... [et al.

2022 Volume 71, Issue 5-6, Page(s) 711–722

Abstract: Objective: Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, ...

Abstract	Objective: Sitagliptin and other dipeptidyl peptidase (DPP)-4 inhibitors/gliptins are antidiabetic drugs known to improve lipid profile, and confer anti-inflammatory and anti-fibrotic effects, which are independent of their hypoglycemic effects. However, in our previous short-term (35 days) studies, we showed that sitagliptin accentuates the hepato-inflammatory effects of high dietary cholesterol (Cho) in male Sprague-Dawley rats. Since most type 2 diabetics also present with lipid abnormalities and use DPP-4 inhibitors for glucose management, the present study was conducted to assess the impact of sitagliptin during long-term (98 days) feeding of a high Cho diet. An additional component of the present investigation was the inclusion of other gliptins to determine if hepatic steatosis, necro-inflammation, and fibrosis were specific to sitagliptin or are class effects. Methods: Adult male Sprague-Dawley rats were fed control or high Cho (2.0%) diets, and gavaged daily (from day 30 through 98) with vehicle or DPP-4 inhibitors (sitagliptin or alogliptin or saxagliptin). On day 99 after a 4 h fast, rats were euthanized. Blood and liver samples were collected to measure lipids and cytokines, and for histopathological evaluation, determination of hepatic lesions (steatosis, necrosis, inflammation, and fibrosis) using specific staining and immunohistochemical methods. Results: Compared to controls, the high Cho diet produced a robust increase in NASH like phenotype that included increased expression of hepatic (Tnfa, Il1b, and Mcp1) and circulatory (TNFα and IL-1β) markers of inflammation, steatosis, necrosis, fibrosis, and mononuclear cell infiltration. These mononuclear cells were identified as macrophages and T cells, and their recruitment in the liver was facilitated by marked increases in endothelium-expressed cell adhesion molecules. Importantly, treatment with DPP-4 inhibitors (3 tested) neither alleviated the pathologic responses induced by high Cho diet nor improved lipid profile. Conclusions: The potential lipid lowering effects of DPP-4 inhibitors were diminished by high Cho (a significant risk factor for inducing liver damage). The robust inflammatory responses induced by high Cho feeding in long-term experiment were not exacerbated by DPP-4 inhibitors and a consistent hepatic inflammatory environment persisted, implying a prospective physiological adaptation.
MeSH term(s)	Animals ; Cholesterol, Dietary ; Diabetes Mellitus, Type 2/drug therapy ; Diet ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Fibrosis ; Hypercholesterolemia ; Hypoglycemic Agents ; Inflammation/pathology ; Male ; Necrosis/drug therapy ; Prospective Studies ; Rats ; Rats, Sprague-Dawley ; Sitagliptin Phosphate/pharmacology ; Sitagliptin Phosphate/therapeutic use
Chemical Substances	Cholesterol, Dietary ; Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents ; Sitagliptin Phosphate (TS63EW8X6F)
Language	English
Publishing date	2022-05-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1221794-3
ISSN	1420-908X ; 1023-3830
ISSN (online)	1420-908X
ISSN	1023-3830
DOI	10.1007/s00011-022-01572-4
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ab Jg. 2022: Lesesaal (EG)

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Article: High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats.

Kumar, Avinash / Pathak, Rashmi / Palfrey, Henry A / Stone, Kirsten P / Gettys, Thomas W / Murthy, Subramanyam N

Nutrition & metabolism

2020 Volume 17, Page(s) 2

Abstract: Background: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. ... ...

Abstract	Background: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. Methods: Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35 days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. Results: The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. Conclusion: Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.
Language	English
Publishing date	2020-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2160376-5
ISSN	1743-7075
ISSN	1743-7075
DOI	10.1186/s12986-019-0422-z
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Article: High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats

Kumar, Avinash / Pathak, Rashmi / Palfrey, Henry A / Stone, Kirsten P / Gettys, Thomas W / Murthy, Subramanyam N

Nutrition & metabolism. 2020 Dec., v. 17, no. 1

2020

Abstract: BACKGROUND: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. ... ...

Abstract	BACKGROUND: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. METHODS: Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35 days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. RESULTS: The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. CONCLUSION: Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.
Keywords	Western diets ; ad libitum feeding ; cholesterol ; collagen ; fatty liver ; fibrosis ; hepatotoxicity ; homocysteine ; hypercholesterolemia ; hypoglycemic agents ; immunohistochemistry ; laboratory animals ; liver ; males ; methionine ; oxidative stress ; rats ; risk factors ; staining
Language	English
Dates of publication	2020-12
Size	p. 2.
Publishing place	BioMed Central
Document type	Article
ISSN	1743-7075
DOI	10.1186/s12986-019-0422-z
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Hepatic

Fang, Han / Stone, Kirsten P / Ghosh, Sujoy / Forney, Laura A / Sims, Landon C / Vincik, LeighAnn / Gettys, Thomas W

Nutrients

2021 Volume 13, Issue 6

Abstract: The principal sensing of dietary methionine restriction (MR) occurs in the liver, where it activates multiple transcriptional programs that mediate various biological components of the response. ... ...

Abstract	The principal sensing of dietary methionine restriction (MR) occurs in the liver, where it activates multiple transcriptional programs that mediate various biological components of the response. Hepatic
MeSH term(s)	Adiposity ; Animals ; Body Weight ; Energy Metabolism ; Fibroblast Growth Factors/metabolism ; Genotype ; Liver/metabolism ; Male ; Methionine/administration & dosage ; Methionine/deficiency ; Methionine/metabolism ; Mice ; Mice, Inbred C57BL ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Obesity/diet therapy ; Phenotype
Chemical Substances	NF-E2-Related Factor 2 ; fibroblast growth factor 21 ; Fibroblast Growth Factors (62031-54-3) ; Methionine (AE28F7PNPL)
Language	English
Publishing date	2021-05-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13061788
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