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Diet-gene interactions and PUFA metabolism: a potential contributor to health disparities and human diseases.

Chilton FH, Murphy RC, Wilson BA, Sergeant S, Ainsworth H, Seeds MC, Mathias RA - Nutrients (2014)

Bottom Line: Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD).Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints.These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

View Article: PubMed Central - PubMed

Affiliation: The Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. schilton@wakehealth.edu.

ABSTRACT
The "modern western" diet (MWD) has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6) 18 carbon (C18), polyunsaturated fatty acid (PUFA) linoleic acid (LA; 18:2n-6), with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD). Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

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LCPUFA Cellular Metabolism. The incorporation of LCPUFAs into phospholipids and their release occur by a complex network of enzymatic activities and related genes. Free fatty acids are activated by conjugation with Coenzyme A (CoA) by gene products derived from up to five genes before incorporation into and remodelling through various phospholipids by enzymes differing in both LCPUFA and phospholipid acceptor specificities. Upon cell activation, phospholipases (A2, C and D) cleave esterified fatty acids from membrane phospholipids. Certain LCPUFAs (such as ARA) can then act as substrates for the eicosanoid-generating enzymes COX1/2, ALOX and P450.
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nutrients-06-01993-f002: LCPUFA Cellular Metabolism. The incorporation of LCPUFAs into phospholipids and their release occur by a complex network of enzymatic activities and related genes. Free fatty acids are activated by conjugation with Coenzyme A (CoA) by gene products derived from up to five genes before incorporation into and remodelling through various phospholipids by enzymes differing in both LCPUFA and phospholipid acceptor specificities. Upon cell activation, phospholipases (A2, C and D) cleave esterified fatty acids from membrane phospholipids. Certain LCPUFAs (such as ARA) can then act as substrates for the eicosanoid-generating enzymes COX1/2, ALOX and P450.

Mentions: Once LCPUFAs are synthesized or obtained from the diet, they are transported to cells and tissues in circulation as free fatty acids bound to albumin or esterified to complex lipids such as phospholipids, cholesterol esters, and triglycerides in lipoprotein particles [59]. A great deal remains unknown as to how LCPUFAs move through cellular membranes into the cell. However, once inside, they are acted upon by specific LCPUFA CoA synthetase(s) that converts free LCPUFA into LCPUFA-CoA to be utilized by LCPUFA-CoA: l-acyl-2-lysophosphoglyceride acyltransferase(s) to yield 1-acyl-2-LCPUFA phospholipids (Figure 2) [60,61]. The ACSL4 gene is of particular interest in regard to the former activity as its gene product prefers LCPUFAs, with its specific activity being five-fold higher for ARA than for 18:1, n-9 [62]. With regard to the latter acyltransferase step, MBOAT7 encodes for an enzyme activity that selectively incorporates LCPUFAs into lyso-phosphatidylinositol. In contrast, LPCAT3 encodes an activity with broad specificity for lyso phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), but high activity for LCPUFAs [63]. There are several other CoA-dependent and CoA-independent enzymatic activities that may be responsible for the acylation of individual molecular species of a phospholipid class [64]. Of particular interest is a CoA-independent transacylase activity which catalyzes the remodeling of LCPUFAs from diacyl- to 1-alkyl and 1-alk-enyl-linked phospholipids. Additionally, a calcium-independent phospholipase A2 (PLA2), encoded by PLA2G6A, is a key enzyme that has been proposed to participate in the remodeling of LCPUFAs through membrane phospholipids [61]. Due to the complexity of these pathways, these participating enzymes and their genes unfortunately are often ignored. However, they will be critical to understanding diet-gene interactions as they control the degree to which dietary or synthesized LCPUFAs are made bioavailable for the signaling processes described below.


Diet-gene interactions and PUFA metabolism: a potential contributor to health disparities and human diseases.

Chilton FH, Murphy RC, Wilson BA, Sergeant S, Ainsworth H, Seeds MC, Mathias RA - Nutrients (2014)

LCPUFA Cellular Metabolism. The incorporation of LCPUFAs into phospholipids and their release occur by a complex network of enzymatic activities and related genes. Free fatty acids are activated by conjugation with Coenzyme A (CoA) by gene products derived from up to five genes before incorporation into and remodelling through various phospholipids by enzymes differing in both LCPUFA and phospholipid acceptor specificities. Upon cell activation, phospholipases (A2, C and D) cleave esterified fatty acids from membrane phospholipids. Certain LCPUFAs (such as ARA) can then act as substrates for the eicosanoid-generating enzymes COX1/2, ALOX and P450.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042578&req=5

nutrients-06-01993-f002: LCPUFA Cellular Metabolism. The incorporation of LCPUFAs into phospholipids and their release occur by a complex network of enzymatic activities and related genes. Free fatty acids are activated by conjugation with Coenzyme A (CoA) by gene products derived from up to five genes before incorporation into and remodelling through various phospholipids by enzymes differing in both LCPUFA and phospholipid acceptor specificities. Upon cell activation, phospholipases (A2, C and D) cleave esterified fatty acids from membrane phospholipids. Certain LCPUFAs (such as ARA) can then act as substrates for the eicosanoid-generating enzymes COX1/2, ALOX and P450.
Mentions: Once LCPUFAs are synthesized or obtained from the diet, they are transported to cells and tissues in circulation as free fatty acids bound to albumin or esterified to complex lipids such as phospholipids, cholesterol esters, and triglycerides in lipoprotein particles [59]. A great deal remains unknown as to how LCPUFAs move through cellular membranes into the cell. However, once inside, they are acted upon by specific LCPUFA CoA synthetase(s) that converts free LCPUFA into LCPUFA-CoA to be utilized by LCPUFA-CoA: l-acyl-2-lysophosphoglyceride acyltransferase(s) to yield 1-acyl-2-LCPUFA phospholipids (Figure 2) [60,61]. The ACSL4 gene is of particular interest in regard to the former activity as its gene product prefers LCPUFAs, with its specific activity being five-fold higher for ARA than for 18:1, n-9 [62]. With regard to the latter acyltransferase step, MBOAT7 encodes for an enzyme activity that selectively incorporates LCPUFAs into lyso-phosphatidylinositol. In contrast, LPCAT3 encodes an activity with broad specificity for lyso phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), but high activity for LCPUFAs [63]. There are several other CoA-dependent and CoA-independent enzymatic activities that may be responsible for the acylation of individual molecular species of a phospholipid class [64]. Of particular interest is a CoA-independent transacylase activity which catalyzes the remodeling of LCPUFAs from diacyl- to 1-alkyl and 1-alk-enyl-linked phospholipids. Additionally, a calcium-independent phospholipase A2 (PLA2), encoded by PLA2G6A, is a key enzyme that has been proposed to participate in the remodeling of LCPUFAs through membrane phospholipids [61]. Due to the complexity of these pathways, these participating enzymes and their genes unfortunately are often ignored. However, they will be critical to understanding diet-gene interactions as they control the degree to which dietary or synthesized LCPUFAs are made bioavailable for the signaling processes described below.

Bottom Line: Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD).Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints.These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

View Article: PubMed Central - PubMed

Affiliation: The Center for Botanical Lipids and Inflammatory Disease Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. schilton@wakehealth.edu.

ABSTRACT
The "modern western" diet (MWD) has increased the onset and progression of chronic human diseases as qualitatively and quantitatively maladaptive dietary components give rise to obesity and destructive gene-diet interactions. There has been a three-fold increase in dietary levels of the omega-6 (n-6) 18 carbon (C18), polyunsaturated fatty acid (PUFA) linoleic acid (LA; 18:2n-6), with the addition of cooking oils and processed foods to the MWD. Intense debate has emerged regarding the impact of this increase on human health. Recent studies have uncovered population-related genetic variation in the LCPUFA biosynthetic pathway (especially within the fatty acid desaturase gene (FADS) cluster) that is associated with levels of circulating and tissue PUFAs and several biomarkers and clinical endpoints of cardiovascular disease (CVD). Importantly, populations of African descent have higher frequencies of variants associated with elevated levels of arachidonic acid (ARA), CVD biomarkers and disease endpoints. Additionally, nutrigenomic interactions between dietary n-6 PUFAs and variants in genes that encode for enzymes that mobilize and metabolize ARA to eicosanoids have been identified. These observations raise important questions of whether gene-PUFA interactions are differentially driving the risk of cardiovascular and other diseases in diverse populations, and contributing to health disparities, especially in African American populations.

Show MeSH
Related in: MedlinePlus