Effects of Dietary Amino Acids on Serum and Macrophage Atherogenicity

June 7, 2017 updated by: Prof. Tony hayek MD, Rambam Health Care Campus
Recently, the investigators have been screening for anti-atherogenic or pro-atherogenic amino acids (AAs) in the macrophage model system to better understand their role in atherogenesis. The findings so far suggest that specific AAs induce selective anti-atherogenic effects (glycine, alanine, leucine and cysteine) or pro-atherogenic effects (glutamate and glutamine) in macrophages. Taking together the above previous reports with the mechanisms behind macrophage foam cell formation and atherogenesis, it is possible that AAs could be anti-atherogenic or pro-atherogenic via their mechanism of action on macrophage foam cell formation. This paradigm may serve as a basis for the development of novel cardio-protective, anti-atherogenic nutritional, or therapeutic approaches, that should be studied in human trials.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Atherosclerosis is the underlying cause of cardiovascular diseases (CVD), the major cause of death worldwide. Atherosclerosis is an inflammatory disease of the arteries in which activated macrophages are abundant in the atherosclerotic lesions. Macrophages play key roles during early atherogenesis. After differentiating from peripheral blood monocytes, the formed intimal macrophages take up oxidized/modified lipoproteins and are transformed into lipid-rich foam cells, the hallmark feature of early atherogenesis. In addition to lipoprotein uptake, lipid accumulation in macrophages can also result from alterations in cellular lipid metabolism, e.g. attenuated reverse lipid transport or enhanced rates of lipid biosynthesis. Although much progress has been made in understanding the role of different lipids (fatty acids, cholesterol, phospholipids or triglycerides) in macrophage foam-cell formation and atherosclerosis development, little is known about the potential impact of other nutrients, such as amino acids (AAs).

Previous studies have demonstrated an association between specific AAs and increased CVD risk or higher prevalence of coronary artery disease (CAD). For instance, the role of the branched chain AAs (BCAAs; valine, leucine, and isoleucine) in atherogenesis and CVD has been recently studied. Association studies showed that the plasma levels of BCAAs significantly and independently correlated with dyslipidemia and CAD. However, BCAAs were found to possess cardio-protective effects in a heart failure rat model. Specifically, leucine was reported to attenuate atherosclerosis development in the atherosclerotic apoE-deficient (apoE-/-) mice model, by improving the plasma lipid profile and by reducing systemic inflammation. Other studies have indicated the ability of some AAs to exert anti-atherogenic effects. Glycine, the simplest AA, was inversely associated with the risk of acute myocardial infarction (AMI) in patients with high apolipoprotein B (apoB) and LDL-cholesterol levels. Cysteine is an essential AA in the biosynthesis of glutathione, a key endogenous anti-oxidant known for its anti-atherogenic properties in macrophage lipid metabolism leading to the attenuation of atherosclerosis development. Cysteine analogues such as N-acetyl cysteine (NAC) or ribose cysteine were shown to be anti-atherogenic. Arginine, a basic AA, is the main precursor for nitric oxide production in the vascular endothelium. Arginine was shown to protect endothelial cells from lipid peroxidation, and to delay or reduce atheroma formation. Arginine anti-atherogenicity includes its anti-oxidant properties and its ability to improve endothelial function in CVD or overweight patients.

The aim of the proposed study is to investigate the effects of one month of supplementation with specific AAs on changes in the macrophage atherogenicity and lipid metabolism together with other risk markers of atherosclerosis development, such as serum oxidative status and lipid levels, on healthy subjects. Findings from the current proposed study may shed light on yet unknown mechanisms by which specific AAs affect atherosclerosis development and CVD risk and hence could possibly assist in the future development of anti-atherogenic strategies

Study Type

Interventional

Enrollment (Anticipated)

110

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 48 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • healthy adult males between the ages of 18-50 after signing informed consent

Exclusion Criteria:

  • pregnancy, renal, pulmonary, cardiovascular or endocrinal diseases, diabetes, cancer, morbid obesity (body mass index, BMI > 40 kg/m2), heavy smoking (> 20 cigarettes/day), or consumption of more than two alcoholic drinks per day. Subjects from the same hospital unit or from the laboratory where this study is conducted are also excluded

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Sham Comparator: Control
Other: Cellulose (control): cellulose, water soluble powder, 2 g in one daily dose, during 30 days
Other: Cellulose (control)
Cellulose (a vegetal product, in powder form, used as dietary fiber, that is not digested or absorbed in the intestines), will be supplemented in the form of water soluble powder.
Experimental: Glycine (Trade name: Glycine)
Dietary Supplement: Glycine, water soluble powder, 7.8 g daily in one dose, during 30 days.
Dietary supplement: Glycine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glycine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: Glycine (Manufacturer Fagron Inc)
Experimental: Alanine (Trade name: L-Alanine)
Dietary Supplement: Alanine, water soluble powder, 8.5 g daily in one dose, during 30 days.
Dietary supplement: Alanine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Alanine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Alanine (Manufacturer Fagron Inc)
Experimental: Leucine (Trade name: L-Leucine)
Dietary Supplement: Leucine, water soluble powder, 14 g daily in one dose, during 30 days.
Dietary supplement: Leucine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Leucine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Leucine (Manufacturer Fagron Inc)
Experimental: Isoleucine (Trade name: L-Isoleucine)
Dietary Supplement: Isoleucine, water soluble powder, 8.2 g daily in one dose, during 30 days.
Dietary supplement: Isoleucine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Isoleucine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Isoleucine (Manufacturer Fagron Inc)
Experimental: Valine (Trade name: L-Valine)
Dietary Supplement: Valine, water soluble powder, 9 g daily in one dose, during 30 days.
Dietary supplement: Valine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Valine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Valine (Manufacturer Fagron Inc)
Experimental: Cysteine (Trade name: L-Cysteine)
Dietary Supplement: Cysteine, water soluble powder, 2.2 g daily in one dose, during 30 days.
Dietary supplement: Cysteine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Cysteine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Cysteine (Manufacturer Fagron Inc)
Experimental: Arginine (Trade name: L-Arginine)
Dietary Supplement: Arginine, water soluble powder, 10 g daily in one dose, during 30 days.
Dietary supplement: Arginine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Arginine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Arginine (Manufacturer Fagron Inc)
Experimental: Methionine (Trade name: DL-Methionine)
Dietary Supplement: Methionine, water soluble powder, 4 g daily in one dose, during 30 days.
Dietary supplement: Methionine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Methionine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: DL-Methionine (Manufacturer Fagron Inc)
Experimental: Glutamate (Trade name: L-Glutamic acid)
Dietary Supplement: Glutamate, water soluble powder, 33 g daily in one dose, during 30 days.
Dietary supplement: Glutamate
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glutamate will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Glutamic acid (Manufacturer Fagron Inc)
Experimental: Glutamine (Trade name: L-Glutamine)
Dietary Supplement: Glutamine, water soluble powder, 30 g daily in one dose, during 30 days.
Dietary supplement: Glutamine
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glutamine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
Other Names:
  • Trade name: L-Glutamine (Manufacturer Fagron Inc)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum atherogenicity
Time Frame: 1 year
Macrophage lipids (triglycerides and cholesterol) content (μg/mg cell protein) following incubation with serum derived from the subjects.
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum triglyceride concentration
Time Frame: 1 year
Triglyceride concentration (mg/dL) vs control group
1 year
Macrophage cholesterol content
Time Frame: 1 year
Cholesterol concentration (mg/dL) vs control group
1 year
Serum oxidation
Time Frame: 1 year
Serum levels of thiobarbituric acid reactive substances (TBARS)
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rambam Health Care Campus

Investigators

  • Principal Investigator: Tony Hayek, Prof, Rambam Health Care Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

July 1, 2017

Primary Completion (Anticipated)

December 15, 2017

Study Completion (Anticipated)

May 1, 2018

Study Registration Dates

First Submitted

May 25, 2017

First Submitted That Met QC Criteria

June 7, 2017

First Posted (Actual)

June 8, 2017

Study Record Updates

Last Update Posted (Actual)

June 8, 2017

Last Update Submitted That Met QC Criteria

June 7, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0566-16-RMB CTIL

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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