The French Paradox - Red Wine, OX-LDL, Resveratrol, and Procyanidins
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
The French Paradox
How dare they - eat croissants dripping in full fat butter, guzzle great red wine, and enjoy 2 hour long 5 course meals loaded with fat. And yet, they do not seem to suffer the fate of many Americans.
“LOX-1 is known as the Oxidized LDL receptor, and is responsible, in large part for depositing what we know as ‘plaque’ on arterial walls.”
Oxidization of LDL - PON Genes Step In For Us
Most of us get that LDL, is the ‘bad’ cholesterol, and that when it gets oxidized, its even worse.
A series of genes - the PON genes (PON1, PON2, PON3) help protect LDL from getting oxidized.
PON genes are transcribed and regulated mostly by PPAR-Gamma. Co factor is calcium, but not heme!
Statins increase PON1 activity. And there are many natural alternatives! Inflammatory cytokines (TNFA, IL-1B, etc) suppress PON1 activity as do the presence of heavy metals.
LOX-1 - The Oxidized LDL Receptor
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), one of the scavenger receptors for oxidized low-density lipoprotein cholesterol (ox-LDL), plays a crucial role in the uptake of ox-LDL by cells in the arterial wall.
Mounting evidence suggests a role for LOX-1 in various steps of the atherosclerotic process, from initiation to plaque destabilization.
Studies of the genetic structure of LOX-1 have also uncovered various genetic polymorphisms that could modulate the risk of atherosclerotic cardiovascular events.
As evidence supporting the vital role of LOX-1 in atherogenesis keeps accumulating, there is growing interest in LOX-1 as a potential therapeutic target.
A compound known as Procyanidins, are potent inhibitors of LOX-1
PON Genes - The Details
The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that share considerable structural homology and are located adjacently on chromosome 7 in humans. By far the most-studied member is PON1, a high-density lipoprotein-associated esterase/lactonase, also endowed with the capacity to hydrolyze organophosphates, but all the three proteins prevent oxidative stress and fight inflammation. They therefore seem central to a wide variety of human illnesses, including atherosclerosis, diabetes mellitus, mental disorders and inflammatory bowel disease. The major goal of this review is to highlight the regulation of each of the paraoxonase components by diverse nutritional molecules and pharmacological agents as well as a number of pathophysiological events, such as oxidative stress and inflammation. Considerable and detailed cell-based studies and animal model experiments have been provided to allow a thorough scrutiny of PON modulation, which will increase our understanding and ability to target these genes in order to efficiently increase their transcriptional activity and decrease the risks of developing different disorders.[3]
PON1 (Paraoxonase 1) is a Protein Coding gene. Diseases associated with PON1 include Microvascular Complications Of Diabetes 5 and Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 7[2]
Mostly expressed in the liver and secreted to the plasma. Bound to HDL particles. Hydrolyzes lipid peroxides, lactones; antixoidant and anti atherosclerotic. It intervenes, and protects LDL from being oxidized from hydrogen peroxide in the plasma - which is a job shared by GPX3.
PON2 is ubiquitously expressed, intracellularly, Endoplasmic Reticulum, and in the mitochondria. Similar action as PON1, but located in different places.
PON3 - expressed heavily in liver, kidneys, and other tissues too. HDL bound. More potent than PON1 in protection of LDL from being oxidized.
The main transcription factors that stimulate PON genes are: PPAr-Gamma, .SP1, HNF-1A, HNF-4a, LXR (Liver X Receptor), AP-1. Interestingly AhR, can suppress PON1 under toxic stress!
The paraoxonase (PON) gene family contains three different members (PON1, PON2 and PON3), and exhibits antioxidative properties principally in the blood circulation. Recent interests have been directed towards a better comprehension of the functions of PON2 and PON3, but PON1 remains by far the most studied of the three enzymes.
All three PONs seem to be important players in the maintenance of a low oxidative state in the blood circulation and, therefore, the prevention of atherosclerosis. Associations of their polymorphisms with various human diseases show a potential implication of these enzymes in other organs. Of note, PON1 gene polymorphisms have been shown to account for more than 60% of the interindividual variation in enzyme concentration and activity but the three PONs have shown to be modulated by various nutritional and pharmacological molecules and some pathophysiological events such as inflammation and oxidative stress. The purpose of this review is to summarize and update of the major functions attributed to PONs, as well as the nutritional, physiological and pharmacological influences of PON expression and activity in relation to disease. Identifying lifestyle modifications that favor PON expression and activity could have a major impact on atherosclerosis and many other oxidative stress-related diseases. In addition, the discovery of pharmacological products that modulate PONs could be of major clinical importance.
Physiological roles of PON1
PON1 was first studied for its capacity to detoxify organophosphate compounds, but the current paper will focus primarily on its antioxidative and anti-inflammatory properties as well as on the potential pathophysiological implications of its modulation.
HDLs are the most powerful independent negative predictors of cardiovascular events. The protective effects of HDLs have first been attributed to their capacity to promote cellular cholesterol efflux from peripheral cells.
Paraoxonase-1 (PON1) is a high-density lipoprotein-associated esterase and is speculated to play a role in several human diseases including diabetes mellitus and atherosclerosis. Low PON1 activity has been associated with increased risk of major cardiovascular events, therefore a variety of studies have been conducted to establish the cardioprotective properties and clinical relevance of PON1. [1] Statins increase PON1 activity. And there are many natural alternatives! Inflammatory cytokines (TNFA, IL-1B, etc) suppress PON1 activity as do the presence of heavy metals.
PON1 is a calcium-dependent esterase that was first described for its capacity to hydrolyze organophosphates and pesticides, including paraoxon, which inspired the name of the three enzymes. PON1 is a 43–45 kDa glycoprotein, expressed in a variety of tissues, but it is mainly synthesized by the liver and circulates within high-density lipoprotein (HDL) particles. It has been the focus of more intense research activities, because of its evident capacity to protect low-density lipoproteins (LDL) against oxidative stress, reduce macrophage foam cell formation and prevent atherosclerosis development. PON1 gene polymorphisms have been associated with various human diseases, including coronary heart disease, Parkinson's disease, type 2 diabetes and inflammatory bowel disease.
PON1 - A Longevity Gene!
Paraoxonase 1 (PON1) is one of the most studied genes regarding cardiovascular risk, oxidative stress and inflammation. Several lines of evidence suggests that PON1 promotes an atheroprotective effect. Patients carrying PON1 codon 192 QQ genotype display a higher risk of cardiovascular events, the major cause of mortality in the elderly: it can be predicted that gene variants increasing the risk of mortality will be under-represented in long-living individuals. We first reported that PON1 R allele (R+) carriers are significantly more represented in Italian centenarians; subsequently this topic has been addressed by many other groups, and here we report a meta-analysis on 11 studies in different populations selected by a review of the literature available in PubMed and testing the effect of the Q192R polymorphism on human ageing. QUORUM guidelines for meta-analysis have been followed, and a total number of 5962 subjects have been included: 2795 young controls (<65 years of age) and 3167 old subjects (>65 years of age). The Mantel-Haenszel weighting for pooling in presence of a fixed effects model has been applied.
The meta-analysis of R carriers showed a significant result with an overall OR of 1.16 (1.04–1.30, 95% CI, p = 0.006). The meta-analysis of QR genotype also showed a significant result, with an overall OR of 1.14 (1.02–1.27, 95% CI, p = 0.016).
The results show that PON1 gene variants at codon 192 impact on the probability of attaining longevity, and that subjects carrying RR and QR genotypes (R+ carriers) are favoured in reaching extreme ages. These results likely represent the counterpart of the effects observed on cardiovascular diseases (CVD), as centenarians and nonagenarians escaped or delayed the onset of the major age-related diseases, including CVD.[5]
Physiological roles of PON2
Less information is available regarding the specific functions and regulation of PON2. However, like PON1, it has been implicated in oxidative stress, inflammation and quorum-sensing regulation. Its antioxidative properties may be related to atherosclerosis prevention, although PON2 protein is not detectable in HDL particles. However, PON2 is expressed in nearly all human tissues with a primary localization in the plasma membrane, which suggests functions that are distinct from those reported.
Despite increasing interest in PON2, there is still little information about its functions and characteristics. Although this member of the PON family does not associate with HDL particles in the circulation, it has also been involved in the reduction of oxidative stress and protection against atherosclerosis. PON2 is expressed in nearly all human tissues, including the lungs, liver, heart and intestine. In vascular cells, PON2 was found to be a cell-based enzyme and appeared in two glycosylated isoforms of approximately 40–43 kDa . PON2 gene polymorphisms have been implicated in a variety of human disorders, such as cardiovascular diseases, type 2 diabetes, and inflammatory bowel disease.
Physiological roles of PON3
The biological functions of PON3 were clarified with the pioneer work of Draganov et al. in 2000 [181]. Characterization of rabbit PON3 was carried out following its purification and it interestingly co-purified with PON1 and apo A-I, both known components of HDL, indicating the location of PON3 within HDL particles. Substrate specificity was found to be quite different, as PON3 had no paraoxonase activity and very limited arylesterase activity, but was endowed with a much greater lactonase.
PON3, the third member of the multigene family, is similar to PON1 in terms of expression, function and location. Both recombinant human PON1 and PON3 show the capacity to delay LDL oxidation in vitro, with PON1 being more effective than PON3 in this respect. Few data are available for the moment on PON3 polymorphisms and the effects of these variants on human diseases are still unknown.
The paraoxonase (PON) gene family (including PON1, PON2, and PON3), is known for its anti-oxidative and anti-inflammatory properties, protecting against metabolic diseases such as obesityand metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the influence of commonandrare PON variants on both conditions was investigated. A total of 507 healthy weight individuals and 744 patients with obesity including 433 with histological liver assessment, were sequenced with single-molecule molecular inversion probes (smMIPs), allowing the identification of genetic contributions to obesity and MASLD-related liver features. Polymorphisms rs705379 and rs854552 in the PON1 gene displayed significant association with MASLD stage and fibrosis, respectively. Additionally, rare PON1 variants were strongly associated with obesity. This study thereby reinforces the genetic foundation of PON1 in obesity and various MASLD-related liver features, by extending previous findings from common variants to include rare variants. Additionally, rare and very rare variants in PON2 were discovered to be associated with MASLD-related hepatic f ibrosis. Notably, we are the first to report an association between naturally occurring rare PON2 variants and MASLD-related liver fibrosis. Considering the critical role of liver fibrosis in MASLD outcome, PON2 emerges as a possible candidate for future research endeavors including exploration of biomarker potential.[4]
LOX1 - The French Paradox
Lectin-like oxidized LDL receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL (oxLDL) and plays multiple roles in the development of cardiovascular diseases. We screened more than 400 foodstuff extracts for identifying materials that inhibit oxLDL binding to LOX-1. Results showed that 52 extracts inhibited LOX-1 by more than 70% in cell-free assays. Subsequent cell-based assays revealed that a variety of foodstuffs known to be rich in procyanidins such as grape seed extracts and apple polyphenols, potently inhibited oxLDL uptake in Chinese hamster ovary (CHO) cells expressing LOX-1. Indeed, purified procyanidins significantly inhibited oxLDL binding to LOX-1 while other ingredients of apple polyphenols did not. Moreover, chronic administration of oligomeric procyanidins suppressed lipid accumulation in vascular wall in hypertensive rats fed with high fat diet. These results suggest that procyanidins are LOX-1 inhibitors and LOX-1 inhibition might be a possible underlying mechanism of the well-known vascular protective effects of red wine, the French Paradox.[6]
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), one of the scavenger receptors for oxidized low-density lipoprotein cholesterol (ox-LDL), plays a crucial role in the uptake of ox-LDL by cells in the arterial wall. Mounting evidence suggests a role for LOX-1 in various steps of the atherosclerotic process, from initiation to plaque destabilization. Studies of the genetic structure of LOX-1 have also uncovered various genetic polymorphisms that could modulate the risk of atherosclerotic cardiovascular events. As evidence supporting the vital role of LOX-1 in atherogenesis keeps accumulating, there is growing interest in LOX-1 as a potential therapeutic target. [7]
The scavenger receptor LOX-1 is an important player in the development of atherosclerosis and its sequelae, such as acute myocardial infarction and cardiac remodeling. It activates most, if not all, signaling pathways from plaque initiation to plaque destabilization. From genetic studies, it is quite evident that certain LOX-1 variations tend to increase the propensity to develop atherosclerosis related events. LOX-1 appears to be a potential novel target in modifying the atherosclerotic pro cess. A host of strategies are being proposed that would either block oxidation of LDL cholesterol or reduce the expression of LOX-1. [7]
LOX-1 is an endothelial receptor for oxidized low-density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis.The basal expression of LOX-1 is low but highly induced under the influence of proinflammatory and prooxidative stimuli in vascular endothelial cells, smooth muscle cells, macrophages, platelets and cardiomyocytes. Multiple lines of in vitro and in vivo studies have provided compelling evidence that LOX-1 promotes endothelial dysfunction and athero genesis induced by oxLDL. The roles of LOX-1 in the development of atherosclerosis, however, are not simple as it had been considered. Evidence has been accumulating that LOX-1 recognizes not only oxLDL but other athero genic lipoproteins, platelets, leukocytes and CRP. As results, LOX-1 not only mediates endothelial dysfunction but contributes to atherosclerotic plaque formation, throm bogenesis, leukocyte infiltration and myocardial infarction, which determine mortality and morbidity from atherosclerosis. Moreover, our recent epidemiological study has highlighted the involvement of LOX-1 in human cardio vascular diseases. [8]
Guess What Wine Has The Highest Concentrations of Procyanidins ?
Red Wine From Southwest France
Red Wine Grown on Sardinia (A Blue Zone)
The "French paradox" refers to the observation that French people, despite consuming a high-fat diet, have lower rates of coronary heart disease (CHD) than populations with similar fat intake but lower red wine consumption. The "French paradox" is linked to the high consumption of red wine, particularly in regions like southwest France and Sardinia, which produce wines rich in procyanidins. Procyanidins are potent LOX-1 inhibitors, and LOX-1 is a key player in the development of atherosclerosis, a condition that leads to CHD. [6]
So What Do We Do ? Besides Red Wine, & Resveratrol ?
Herbs with high procyanidin content include Cinchona, Cinnamon, Hawthorn, and Cat's Claw. Other sources of procyanidins include grape seeds, grape skin, and pine bark (pycnogenol). Additionally, cranberries, blueberries, and black currants are known for their procyanidin content. [8,9]
Red wines are indeed generally higher in procyanidins than resveratrol. Resveratrol is a compound found in the skin of grapes, while procyanidins are primarily found in the seeds and skins of grapes, as well as in some other foods like cocoa and apples. Red wines, especially those made with certain grape varieties like Tannat, Sagrantino, and Petite Sirah, tend to have higher concentrations of procyanidins. [10]
Selection of any supplement or herb should be considered in the context of other factors, that may be contraindicated by genetics, toxic / infection burdens, metabolic functioning, nutritional, and other factors.
References:
[1] Paraoxonase (PON)-1: a brief overview on genetics, structure, polymorphisms and clinical relevance. By Nelusha Shunmoogam, et. al. Vasc Health Risk Management. . 2018 Jun 18;14:137–143. doi: 10.2147/VHRM.S165173. PMCID: PMC6014389 PMID: 29950852[2] www.genecards.com[3] ReviewThe three-gene paraoxonase family: Physiologic roles, actions and regulation. By Louis-Philippe Précourt, et. al. Atherosclerosis. Volume 214, Issue 1, January 2011, Pages 20-36. Https://doi.org/10.1016/j.atherosclerosis.2010.08.076[4] AntiOxidants. A Case–Control Study Supports Genetic Contribution of the PONGeneFamilyinObesity and Metabolic Dysfunction Associated Steatotic Liver Disease. By Evelien Van Dijck, et. al. Antioxidants 2024, 13, 1051. https://doi.org/10.3390/antiox13091051 https://www.mdpi.com/journal/antioxidants[5] Review: PON1 is a longevity gene: Results of a meta-analysis. By Francesco Lescai a b, et. al. Ageing Research Reviews. Volume 8, Issue 4, October 2009, Pages 277-284. https://doi.org/10.1016/j.arr.2009.04.001[6] Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox. By Taichi Nishizuka, et. al. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(3):104-13. doi: 10.2183/pjab.87.104. PMID: 21422743. PMCID: PMC3066543. DOI: 10.2183/pjab.87.104. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(7):431[7] LOX-1 in Atherosclerosis and Myocardial Ischemia: Biology, Genetics, and Modulation. By panelNaga Venkata K. Pothineni MD, et. al. Journal of the American College of Cardiology. Volume 69, Issue 22, 6 June 2017, Pages 2759-2768. The Present and Future. https://doi.org/10.1016/j.jacc.2017.04.010[8] The Discovery of LOX-1, its Ligands and Clinical Significance. By Ryo Yoshimoto, et. al. Cardiovasc Drugs Ther (2011) 25:379–391 DOI 10.1007/s10557-011-6324-6.[9] Determination of Phenolic Compounds, Procyanidins, and Antioxidant Activity in Processed Coffea arabica leaves. By Samuchaya Ngamsuk, et. al. Foods . 2019 Sep 4;8(9):389. doi: 10.3390/foods8090389. Tzou-Chi Huang, Jue-Liang Hsu. PMCID: PMC6769686 PMID: 31487835[10] Regulation of vascular endothelial function by red wine procyanidins: implications for cardiovascular health. By Noorafza Q. Khan, et. al. Tetrahedron. Volume 71, Issue 20, 20 May 2015, Pages 3059-3065. Https://doi.org/10.1016/j.tet.2014.10.078