Next Article in Journal
Bioactive Natural Compounds and Antioxidant Activity of Essential Oils from Spice Plants: New Findings and Potential Applications
Next Article in Special Issue
The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease
Previous Article in Journal
Hapten Design and Monoclonal Antibody to Fluoroacetamide, a Small and Highly Toxic Chemical
Previous Article in Special Issue
Subcutaneous Administration of Apolipoprotein J-Derived Mimetic Peptide d-[113–122]apoJ Improves LDL and HDL Function and Prevents Atherosclerosis in LDLR-KO Mice
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomolecules
Volume 10
Issue 7
10.3390/biom10070987
biomolecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Alcohol–High-Density Lipoprotein Athero-Protective Axis

by
Corina Rosales
,
Baiba K. Gillard
,
Antonio M. Gotto, Jr.
and
Henry J. Pownall
*
Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(7), 987; https://doi.org/10.3390/biom10070987
Submission received: 12 May 2020 / Revised: 22 June 2020 / Accepted: 23 June 2020 / Published: 1 July 2020
(This article belongs to the Special Issue High-Density Lipoprotein (HDL): The Role of Reverse Cholesterol Transport in Human Health and Disease)
Browse Figures
Versions Notes

Abstract

Ingestion of alcohol is associated with numerous changes in human energy metabolism, especially that of plasma lipids and lipoproteins. Regular moderate alcohol consumption is associated with reduced atherosclerotic cardiovascular disease (ASCVD), an effect that has been attributed to the concurrent elevations of plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. More recent evidence has accrued against the hypothesis that raising plasma HDL concentrations prevents ASCVD so that other metabolic processes associated with alcohol consumption have been considered. This review explored the roles of other metabolites induced by alcohol consumption—triglyceride-rich lipoproteins, non-esterified free fatty acids, and acetate, the terminal alcohol metabolite in athero-protection: Current evidence suggests that acetate has a key role in athero-protection but additional studies are needed.

Graphical Abstract

1. Introduction

Plasma levels of low- and high-density lipoprotein-cholesterol (LDL-C, HDL-C) are positive and negative risk factors, respectively, for atherosclerotic cardiovascular disease (ASCVD). Although the former correlation has remained well supported, the salutary qualities of HDL, which have been widely cited, have now been called into question, as reviewed here, through studies in cells, animal models, and human interventional trials. Although statins and proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeting drugs reduce plasma LDL-C concentrations, therapies that raise plasma HDL-C concentrations in a cardio-protective way are still needed to reduce residual ASCVD risk. Although past observational, prospective [1,2,3], and interventional studies [4,5,6] suggest that raising plasma HDL-C levels is athero-protective via multiple mechanisms, evidence against the raising-HDL-is-athero-protective hypothesis continues to accrue: (1) Not all patients with low HDL-C levels present with ASCVD and vice versa. (2) Patients with cholesteryl ester transfer protein (CETP) deficiencies have high plasma HDL-C levels but less cardio-protection than matched CETP-competent patients [7,8]. (3) Apolipoprotein A1 (APOA1) polymorphisms that elevate plasma APOA1 and HDL levels do not reduce ASCVD risk. [9] (4) Loss-of-function variants that raise (endothelial lipase) [10] or lower (adenosine triphosphate (ATP) binding cassette transporter subfamily A member 1 (ABCA1)) [9] HDL-C levels are not associated with reduced or increased ASCVD risk, respectively [9]. (5) Niacin therapy and CETP inhibition raise HDL-C but do not reduce ASCVD events [11,12,13,14]. Although niacin therapy reduced ASCVD in the Coronary Drug Project [15], in patients receiving a statin, niacin increased HDL-C from 35 mg/dL (0.91 mM) to 42 mg/dL (1.08 mM) but did not elicit a demonstrable ASCVD benefit in patients presenting with two components of metabolic syndrome (MetS)—hypertriglyceridemia and a low HDL-C concentration. [13] Thus, most HDL-increasing mechanisms are not athero-protective and, on a background of statin therapy, most HDL-raising interventions do not reduce ASCVD.
These observations provoked new hypotheses about possible mechanistic links between reduced ASCVD [16,17,18,19,20] and increased plasma concentrations of HDL-C, which has three proposed cardio-protective roles; HDL is a putative anti-oxidant, an anti-inflammatory agent, and an acceptor of macrophage free cholesterol (FC) efflux [21,22,23,24]. The anti-oxidant effects of HDL have been called into question because ~90% of the anti-oxidant capacity of plasma is afforded by other proteins that occur at much higher plasma concentrations—fibrinogen, immunoglobulin G, albumin, and the small, water-soluble molecules, uric acid and ascorbate, with albumin being the dominant anti-oxidant. HDL was a minor contributor (∼1–2%) to the anti-oxidant capacity of plasma. [25] The anti-inflammatory effects of HDL are likely indirect and are a cellular response to FC accretion [26,27,28]. Notably, macrophage cholesterol efflux (MCE) to HDL, reassembled HDL, or β-methylcyclodextrin reduces the number of inflammatory markers [29,30]. Thus, the HDL-mediated reduction in inflammation is an indirect consequence of MCE, the initial step in reverse cholesterol transport (RCT).
The current RCT model was formulated following the discovery of lecithin:cholesterol acyltransferase (LCAT), which converts FC to cholesteryl esters (CE). The authors reasoned that LCAT was required to reduce the cytotoxic effects of excess FC in peripheral tissue, including the arterial wall-macrophages where excess FC is likely atherogenic [31]. RCT comprises multiple steps (Figure 1): FC in arterial-wall macrophages transfers to early forms of HDL, i.e., nascent (n) HDL, via (1) the interaction of APOA1 with the ABCA1 transporter or (2) spontaneous FC transfer to nHDL and mature HDL. (3) LCAT esterifies nHDL-FC, which (4) promotes the extrusion of lipid-free APOA1 [32] for recycling to ABCA1. (5) FC and CE transfer to the liver via hepatic scavenger receptor class B member 1 (SCARB1). (6) FC also enters liver cells via spontaneous transfer.
Formation of CE from FC via LCAT is important because this step converts FC, which transfers freely (minutes) among lipoprotein and membrane surfaces, to CE, which does not transfer spontaneously from HDL to peripheral tissue, and transfers slowly (hours) to other lipoproteins via CETP. Hypothetically, this prevents the reverse transfer of cholesterol into peripheral tissue including the arterial wall. Hepatic and steroidogenic tissue extraction of cholesterol via SCARB1 has a unique mechanism. Unlike the LDL receptor, which extracts the entire LDL particle, SCARB1 extracts only lipids [33,34] via a nibbling mechanism that leaves a protein-rich HDL remnant and lipid-free APOA1 [32]. Within the liver, FC is converted to bile acids that are excreted, thereby reducing the FC burden of peripheral tissue, including the arterial wall. In the absence of efficient RCT, cholesterol accumulates in arterial wall-macrophages, a process that precedes formation of cholesterol-rich atherosclerotic lesions. Thus, RCT, which is initiated by MCE, is integral to the athero-protective effects of HDL and APOA1.
However, the extant data remain incomplete and are still debated because others report the opposite or no correlation between MCE and athero-protection [35,36,37,38,39,40]. Below, we reviewed the literature on the effects of alcohol ingestion on HDL metabolism and ASCVD with the goal of developing a refined mechanistic model linking HDL function to ASCVD.

2. Correlating HDL, Alcohol Ingestion, and ASCVD

There are exceptions to the failed raising-HDL-is-athero-protective hypothesis. Both exercise and moderate alcohol consumption increase plasma HDL-C and -phospholipid (PL) concentrations [41,42,43,44,45,46,47], and reduce ASCVD risk [48,49,50,51,52,53]. Two drinks per day increase plasma HDL-C concentrations ~12% [54]. Whereas alcohol ingestion in the context of a typical Western diet induced a dose-dependent increase in HDL-C (≤18%), APOA1 (≤10%), and APOA2 concentrations (≤17%), the fractional clearance rates of APOA1 and APOA2 were not changed. These effects were associated with increased transport of APOA1 and APOA2 [55].
Whereas daily moderate alcohol consumption reduces ASCVD death in a dose-dependent way up to 1 drink/day, high alcohol intake increases death from other causes [56,57]. However, controlling for HDL-C does not affect the magnitude of the relationship between alcohol intake and ASCVD-related death (2011 Cohort of Norway) [58]. Alcohol intake does not affect expression of the major HDL-related genes coding for ABCA1, apolipoprotein A5 (APOA5), CETP, hepatic lipase, and lipoprotein lipase (CoLaus Study) [59]. Thus, the mechanistic links underlying the association between alcohol ingestion and reduced ASCVD remain to be identified—a complicated challenge given the broad effects of alcohol on multiple aspects of energy metabolism. Two hypotheses emerge about the cardio-protective effects of HDL—a direct effect on MCE and transport or a broader but more indirect effect on lipid metabolism.

3. Alcohol Metabolism

Alcohol has multiple pathophysiological effects on whole-body energy metabolism and the plasma lipoprotein profiles that originate in several hepatocyte-specific pathways [60]: Reduced gluconeogenesis lowers plasma glucose levels; lactate production induces plasma lactic acidemia; and sequential oxidation of alcohol forms acetaldehyde, a toxic compound that is then converted to acetate, which enters the plasma compartment. Alcohol-induced increases in hepatic triglyceride (TG) production have two pathological effects—some excess TG is secreted as very-low-density lipoproteins, thereby producing a hypertriglyceridemia, and unsecreted and non-degraded TG is hepatically retained and precedes fatty liver disease.
Given that the consumption of food and alcohol, usually together, are an embedded feature of many cultures, it is not surprising that both are also the subject of research in nearly every context of health and disease. According to 2016 World Health Organization statistics, per capita consumption of pure alcohol in the United States was ~9 L or about 25 quarts of 80-proof alcohol, a value that is slightly higher and lower than the average for men and women, respectively [61]. So, alcohol consumption makes a meaningful contribution to the diet of the average person and understanding its interactions with other environmental factors, especially food, and with genetic factors, is important to the rational design of public health strategies. Whereas alcohol consumption is associated with multiple aspects of lifestyle, meal, physical activities, smoking, culture, races, environment, and age, here we focused on the alcohol–HDL–ASCVD axis.
Hepatic alcohol metabolism is a short, linear, sequence of reactions—alcohol is converted successively to acetaldehyde, acetate, and acetyl-coenzyme A (acetyl-CoA) by alcohol dehydrogenase (ADH1B), acetaldehyde dehydrogenase (ALDH2), and acetyl-CoA synthase (ACSS2), respectively. Once formed, acetyl-CoA is a substrate for the citric acid cycle, ultimately producing cellular energy and releasing water and carbon dioxide. Genetic variants of these enzymes among individuals are associated with differences in catalytic efficiency and their capacity to metabolize alcohol. There are two major polymorphisms in the genes of alcohol metabolism that are relevant to the effects of alcohol on lipid metabolism and, perhaps, ASCVD. Among many East Asians, but not South Asians, acetaldehyde accumulates because they carry an allele of the gene coding for a super-activated alcohol dehydrogenase, a process that is exacerbated by the occurrence of a variant of the mitochondrial aldehyde dehydrogenase 2 variant 2 (ALDH2*2) allele. As a consequence, the pathway to acetate formation is impaired and plasma acetaldehyde concentrations increase, thereby inducing the “Asian flush” [62]. The impaired production of acetate is relevant to the function of many downstream effects of acetate, which enters multiple synthetic and regulatory pathways.

4. Chronic Alcohol Consumption Enhances MCE

With one exception [37], most large studies [21,22,63,64] found that MCE and HDL-particle number better predict reduced ASCVD than does HDL concentration. The role of particle number may be due to simple collision theory; during MCE, FC transfers to particle surfaces and a greater number of particles provides a greater number of surfaces. The correlation between MCE and reduced ASCVD suggests that the quality of HDL, i.e., its capacity to receive free cholesterol from cells, is different across patient populations and a more important ASCVD determinant than HDL concentration alone. This correlation provided the rationale for studies of the effects of alcohol consumption on MCE. Although the magnitude of the effect of MCE varied, all studies found that alcohol consumption by both male and female patients, in most studies ~40 g/day for more than two weeks as beer, spirits, or wine, increased plasma HDL-C and LCAT activity. More importantly, most studies showed that chronic alcohol consumption was associated with enhanced MCE from macrophages to patient plasma [65,66,67,68]. In most instances, the magnitude of MCE correlated with plasma HDL-C concentration. One study also found an attendant increase in HDL-phospholipid [69], likely an important MCE driver given that phospholipids are the essential FC-binding component of membranes and lipoproteins and the major compositional determinant of in vitro MCE [70,71,72], which occurs by both aqueous diffusion and via the macrophage FC transporter, ABCA1 [73,74].

5. Acute Effects of Alcohol Consumption

Although the acute effects of alcohol ingestion on MCE to plasma are not known with certainty, its effects on other aspects of lipid metabolism have been explored. Plasma chylomicrons, which form postprandially, are additional potential acceptors of cellular FC that is ultimately hepatically extracted [75]. Thus, it is expected that the lipemia produced by alcohol ingestion would also be associated with an increase in the MCE of plasma. However, the magnitude of alcohol-induced lipemia is much lower than that induced by an oral fat challenge and comprises mostly very-low-density lipoproteins (VLDL). The effects of consuming alcohol and fat together are expected to be different because preprandial alcohol synergizes with fat ingestion, profoundly increasing both the magnitude and duration of postprandial lipemia. Ingestion of alcohol (50 g) or fat (100 g corn oil) increases plasma triglyceride (TG) concentrations 50% and 100%, respectively. However, when consumed together, plasma TG concentration increases by 250%, a change that exceeds the sum of alcohol and fat consumed separately [76]. This observation was confirmed in another study showing that most of the increase in plasma TG concentration following the co-ingestion of alcohol and fat was due to chylomicron accretion with underlying inhibition of lipoprotein lipase [77]. MCE to whole postprandial plasma via the ABCA1- and SCARB1-dependent pathways is higher than those at baseline (+19 and 8%, respectively). The increase was associated with greater MCE to HDL2 than to HDL3 [78]. Other studies [79] have led to similar results, i.e., the postprandial increase in MCE is relatively small. The role of apolipoprotein B (APOB)-containing lipoproteins in MCE studies is usually ignored; most MCE studies are conducted with APOB-depleted plasma with the tacit assumption that HDL is the main determinant of MCE. However, another study revealed the importance of APOB-containing lipoproteins on MCE [80]. Although HDL is the initial (~20 min) acceptor of MCE, at later times the majority of MCE to plasma is associated with the APOB-containing lipoproteins, which, given their much faster turnover rates, would be expected to clear peripheral tissue-derived cholesterol faster than would HDL alone.
Acutely, alcohol ingestion also modifies the cholesteryl ester transfer activity (CETA) mediated by the cholesteryl ester transfer protein (CETP). Studies under conditions emulating normal-life alcohol consumption with an evening meal and under more strictly controlled clinical conditions gave similar results. In the first study, participants consumed food and alcohol as red wine during their evening meal. Wine consumption vs. mineral water increased postprandial plasma TG-rich lipoproteins’ concentrations and in vitro CE transfer from HDL to APOB-containing lipoproteins and transfer of TG in the opposite direction [81]. Plasma concentrations of total cholesterol, HDL-C and APOA1, APOA2, and APOB were unchanged. Thus, in a social setting, moderate wine consumption is associated with an enhanced exchange of VLDL-TG for HDL-CE.
Another study [82] correlated CETA with the plasma lipid concentrations among normotriglyceridemic (NTG) and mildly hypertriglyceridemic (HTG) volunteers who received alcohol, saturated fat (SAT), and alcohol + SAT in a controlled clinical setting. SAT (35 g/m2 body area) was consumed with and without alcohol (200 mL of a 10% weight for weight (w/w) solution) after an overnight fast. Over the following 10 h, bi-hourly samples were collected and analyzed. According to the area-under-the-curve (AUC) data, plasma cholesterol was unchanged over 10 h. However, alcohol induced an early decline in plasma non-esterified fatty acid (NEFA) concentrations due to inhibition of lipolysis of adipose tissue fat and plasma VLDL-TG, and recovered after ~4h. In contrast, SAT ingestion was followed by increased plasma NEFA due to lipolysis of the dietary fat. The NEFA response of alcohol + SAT was roughly the average of the two taken separately. Plasma TG modestly increased (5–10%) after alcohol ingestion but increased by 50 to 100% following ingestion of SAT and alcohol + SAT. Concurrently, plasma CETA increased as a function of plasma TG concentration following ingestion of SAT, a correlation that was more subdued by the combined alcohol + SAT ingestion. Thus, alcohol-mediated inhibition of HDL-CE transfer to chylomicrons maintains a higher plasma HDL-cholesterol concentration, which is possibly athero-protective. Although the suppressive metabolite underlying this correlation could be acetate, the terminal alcohol metabolite, other factors, including the CETA inhibitor, apolipoprotein F (APOF), are also likely important.
Thus, just as postprandial lipoproteins provide more acceptors for MCE, they also provide more acceptors for CETP-mediated transfer of CE from HDL, which are hepatically extracted faster than HDL. These findings are more generally applicable to persons who consume alcohol on a regular basis. Findings may be different when acute effects are compared among traditional abstainers and regular alcohol consumers because of the effects of alcohol on hepatic cytochrome P450 2E1 (CYP2E1) and cytochrome P450 3A4 (CYP3A4), which in humans work with the alcohol and aldehyde dehydrogenases [83].

6. The Role of Acetate in Alcohol-Mediated Effects on Plasma Lipid Metabolism

Whereas some researchers opine that alcohol, rather than any of its metabolites, is the essential determinant of its cardio-protective effects [84,85], clinical reports and recent studies in cells and genetically altered mice have implicated its terminal metabolite, acetate, in some key aspects of alcohol-determined cardio-protection. The physiological role of acetate in lipolysis was revealed by a study that compared the effects of alcohol (38 mL = 30 g of ethanol in 362 mL water in <15 min) on several relevant measures of alcohol metabolism among NTG and HTG volunteers [86]. The alcohol challenge produced the expected rise in plasma alcohol concentration to ~10 mM in both groups (Figure 2). Within the NTG group, there was a parallel 50% increase in the plasma TG concentration, whereas no significant change was observed among the HTG subjects. However, over the ensuing ~5 h, the plasma concentrations of NEFA, a marker of lipolysis, initially declined and then recovered (Figure 3).
Notably, the higher baseline NEFA levels among HTG vs. NTG volunteers is likely due to their higher rates of adipose-tissue lipolysis, which releases NEFA that are destined for hepatic TG synthesis and very-low-density lipoprotein secretion. Acetate metabolism is rapid; ingestion of 750 mg acetic acid/150 mL of water increases serum acetate (+150%) within 15 min, after which it declines with a half-time (t1/2) of ~15 min) [87]. The kinetics of alcohol-derived acetate are slower, rising to 0.9 and 0.5 mM, respectively, in HTG and NTG subjects, and then declining to 0.4 mM at ~5 h. At this concentration, increased plasma NEFA reveals the resumption of lipolysis. These observations implicate acetate (>0.4 mM) as an anti-lipolytic agent. However, the mechanism is not yet known.
Although no single study readily defines the role of alcohol-derived acetate in human lipid metabolism, there were early clues. Alcohol metabolism begins with its conversion to acetaldehyde and acetate via the successive activities of hepatic alcohol dehydrogenase and aldehyde dehydrogenase 2, respectively, the last reaction producing acetate, which is involved in many common metabolic pathways. Collective consideration of several studies suggests that acetate underlies the effects of alcohol on lipid metabolism. One early study compared the effects of alcohol, acetaldehyde, and acetate, alone or in combination, on lipolysis in isolated rat adipocytes in the basal and norepinephrine-stimulated states [88]. According to the rate of glycerol release, only acetate induced a dose-dependent inhibition of lipolysis. Inhibition of lipolysis by combinations of ethanol and acetaldehyde with acetate was similar to that of acetate alone. Thus, acetate alone was implicated in the inhibitory effects of alcohol on lipolysis observed in vivo.
The orphan G-protein coupled receptor, GPR43, was later identified as a second free fatty acid receptor (FFAR2) on leukocytes for which acetate and other short-chained fatty acids are ligands [89]. FFAR2 is also expressed in adipocytes, which, when treated with acetate, exhibit reduced lipolysis, an effect not observed in FFAR2-/- vs. wild-type mice [90,91]. Moreover, FFAR2 activation by acetate reduces plasma free fatty acid levels, suggesting a potential role in broader aspects of normal lipoprotein metabolism and MetS. In humans, acetate and/or alcohol-derived acetate inhibit both adipose tissue (AT) lipolysis [88,92] and lipoprotein lipase (LPL) [77], leading to a profound lipemic response and dramatic, persistent decreases in the major lipolytic products, NEFA and glycerol. The anti-lipolytic effects of acetate in adipose tissue likely underlies the similar effects of alcohol [77,86], which is converted to acetate. In contrast, the mechanism underlying alcohol-mediated LPL inhibition is not known.

7. Mechanisms Underlying the Alcohol–HDL Athero-Protective Axis

Although the mechanisms linking alcohol consumption to reduced ASCVD are not immediately clear, there are several possibilities. One possibility is improved MCE to plasma. The acute lipemia produced by alcohol ingestion, especially when consumed with fat-containing food, provides more acceptors for MCE and for the rapid transfer of CE from a slowly metabolized FC pool in HDL (t1/2 ~3–5 d) to pools that are rapidly removed—VLDL and chylomicron and its remnants (t < 5 h). The importance of this mechanism seems low because a high plasma TG concentration correlates with a low HDL-C concentration [93], an ASCVD risk factor. On the other hand, regular, moderate (chronic) alcohol consumption increases plasma HDL, a longer-lived plasma pool of acceptors of MCE. Although compelling evidence is sparse and/or anecdotal, alcohol-derived acetate seems the stronger candidate as the agent that is the ultimate cardio-protective effector via improved insulin sensitivity. Acetate and alcohol reduce plasma glycerol and NEFA, an effect attributed to reduced lipolysis [92]. Given that acetate inhibits lipolysis in isolated rat adipocytes [88] via a FFAR2 mechanism [91] and that acetate has profound, cardio-protective effects that are independent of plasma HDL-C levels, plasma HDL-C concentrations are more likely a biomarker of cardio-protection than a mechanistic link. Several observations seem to reduce the importance of HDL in cardio-protection [80]: MCE to whole plasma better correlates with APOB and non-HDL-C concentrations than with HDL-C or APOA1; the magnitude of MCE to whole plasma of MetS patients is greater than that to normolipidemic patients; weight loss among MetS patients reduces the magnitude of MCE to their plasma to that of normolipidemic patients. Given the positive effects of weight loss on ASCVD events, weight loss-associated improvement in blood pressure, plasma TG, LDL-C, non-HDL-C concentrations, and insulin sensitivity must be more important than concurrent reduction in MCE. According to these observations, reducing the levels of the traditional ASCVD risk factors is more important than increasing MCE. In light of the studies reviewed here on the role of alcohol and acetate in vitro, in vivo, and in human clinical trials, elucidating the mechanisms by which acetate promotes athero-protection may provide additional/complementary therapies for ASCVD treatment.

8. A Mechanistic Model Links Alcohol Ingestion to a Cardio-Protective Plasma Lipoprotein Profile

The extant literature on alcohol and lipid metabolism [94] provoked our mechanistic model for the alcohol-mediated induction of a cardio-protective plasma lipoprotein profile (Figure 4). Adipose tissue lipolysis is an important determinant of the plasma lipoprotein profile. Under fasting conditions, the NEFA produced by adipose-tissue (AT) lipolysis (1) enter the plasma compartment (2) from which they are hepatically extracted (3). In the liver, the NEFA are esterified to TG (4), which are incorporated into VLDL that are secreted (5). In plasma, CETP exchanges the VLDL-TG for HDL-CE (6), thereby lowering the cholesterol content of each HDL particle and, with it, the plasma HDL-C concentration. Alcohol-derived acetate inhibits the first step, lipolysis, an effect that is followed by the inhibition of each successive step including the final step, reduction of HDL-C via the VLDL-TG for HDL-CE exchange, which leads to an elevation of plasma HDL-C. This model is supported in part by the negative correlation between plasma HDL-C and TG [93].

9. Acetate in Foods

Apple cider and wine vinegars, produced by fermentation of apple and grape juices, respectively, are in commonly consumed foods—salad dressings, marinades, vinaigrettes, and food preservatives. The sour taste of vinegar is due mostly to its content of acetate, which occurs as acetic acid. Whereas some opine that published clinical data claiming that apple cider vinegar can manage glucose, lipid levels, and weight loss are limited and equivocal, there is a large and convincing body of published studies to the contrary that cite several salutary properties of vinegar—reduction in the gastric emptying rate, improved insulin sensitivity, and reduced postprandial hyperglycemia among insulin-dependent diabetes mellitus patients [95,96,97,98]. Other studies, in normal and diabetic humans, revealed that acetate and/or vinegar ingestion is associated with a multitude of salutary effects, not all of which have been confirmed. These include weight loss, reduced plasma TG, total cholesterol, and LDL-C concentrations, but increased plasma HDL-C concentrations [99] and reduced blood glucose, insulin concentrations, and insulin resistance [100,101,102]. Vinegar also attenuated postprandial glycemia [98,103]. Human studies are supported in part by studies in rodents. In the context of high-fat diet (HFD)-induced metabolic disorders, vinegar ingestion by rats induces satiety and is hypolipidemic, hypoglycemic, anti-obesogenic [104,105], and anti-hypertensive [106], an effect that has not been tested in humans. In rats receiving a HFD, vinegar suppresses obesity-induced oxidative stress by modulating anti-oxidant defense systems and reverses HFD-induced obesity, hyperlipidemia, and oxidative stress [107]. Whereas studies in FFAR2-/- mice show that FFAR2 directly mediates the stimulatory effect of acetate on insulin secretion and protects against islet apoptosis [108], the mechanistic connection between other salutary effects of vinegar/acetate remains to be determined. Thus, it appears that FFAR2 mediates many of the effects of acetate whether it is delivered as acetic acid or in numerous other forms including vinegar from multiple fruit sources. Moreover, acetate is also formed via colonic fermentation of acetogenic fiber [109,110] and inulin [111] and via the hydrolysis of triacetin, a common food additive.

10. Acetate as ASCVD Therapy

After alcohol ingestion, plasma acetate levels increase to millimolar concentrations [112,113]. Some speculate that ASCVD risk is lowered by the regular acetate intake in vinegar-and-oil salad dressings [106], so that the effects of alcohol on lipids, blood pressure, and ASCVD is mediated, in part, through its conversion to acetate and subsequent FFAR2 activation. Before the introduction of modern hypoglycemic agents, vinegar teas were used to control diabetes [106]. Small amounts of vinegar (~25 g) consumed with or without food reduce the glycemic index of carbohydrate-containing food for diabetic and non-diabetic persons [96,114,115]. This has been expressed as lower glycemic index ratings (~30%) [116,117].
Vinegar improves insulin sensitivity in normal and metabolic syndrome subjects [96,97], an effect that would be expected to reduce adipocyte lipolysis, thereby lowering plasma NEFA, hepatic TG production and secretion, and plasma TG levels [118]. Moderate daily alcohol intake is also associated with lower insulin secretion [56,57]. Thus, acetate from alcohol and other sources—dietary fiber, inulin, starch, which are converted to acetate by gut microbiota [112] — could be therapeutic via effects on AT-FFAR2 (Figure 5).

11. Open Questions

Alcohol consumption is associated with numerous pathologies—cancer, pancreatitis, fatty liver diseases, and obesity. The implication of acetate in alcohol-associated pathophysiology provokes several testable hypotheses as follows:
  • Does acetate ingestion molar-equivalently enhance the postprandial lipemia seen with alcohol only?
  • Whereas the lipemia induced by both alcohol and fat consumed separately increases with the magnitude of fasting plasma TG levels, is a similar relationship seen when acetate is consumed with fat-containing food and, if so, are the effects of acetate and fat co-ingestion synergistic or additive?
  • Is the occurrence of obesity-linked diabetes, pancreatitis, and ASCVD among persons with mutation-associated deficiencies in alcohol-metabolizing enzymes different from that of those carrying the metabolically competent alleles?
  • What if any role does the FFAR2 have in the etiology of ASCVD in consumers vs. non-consumers of alcohol and acetate or its precursors?
  • Do molar-equivalent amounts of acetate and alcohol provide similar cardio-protective effects?
Answers to these question in humans and in the appropriate cell and animal models will better define the role of common food additives and possible acetate-based therapeutics in health and disease.

Author Contributions

H.J.P. and C.R. conceptualized the paper. H.J.P. prepared the original draft. B.K.G. provided analysis, review, and editing. A.M.G.J. provided scientific and medical critique. All authors contributed to one or more papers cited in the text and have read and agreed to the published version of the manuscript.

Funding

Supported in part by a grant from the National Institutes of Health (R01 HL129767).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Gofman, J.W.; Young, W.; Tandy, R. Ischemic Heart Disease, Atherosclerosis, and Longevity. Circulation 1966, 34, 679–697. [Google Scholar] [CrossRef] [PubMed]
  2. Williams, P.T.; Feldman, D.E. Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman’s Livermore Cohort. Atherosclerosis 2011, 214, 196–202. [Google Scholar] [CrossRef] [PubMed]
  3. Wilson, P.W.; Abbott, R.D.; Castelli, W.P. High density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arteriosclerosis 1988, 8, 737–741. [Google Scholar] [CrossRef]
  4. Frick, M.H.; Elo, O.; Haapa, K.; Heinonen, O.P.; Heinsalmi, P.; Helo, P.; Huttunen, J.K.; Kaitaniemi, P.; Koskinen, P.; Manninen, V.; et al. Helsinki Heart Study: Primary-Prevention Trial with Gemfibrozil in Middle-Aged Men with Dyslipidemia. New Engl. J. Med. 1987, 317, 1237–1245. [Google Scholar] [CrossRef] [PubMed]
  5. Manninen, V.; Elo, M.O.; Frick, M.H.; Haapa, K.; Heinonen, O.P.; Heinsalmi, P.; Helo, P.; Huttunen, J.K.; Kaitaniemi, P.; Koskinen, P.; et al. Lipid Alterations and Decline in the Incidence of Coronary Heart Disease in the Helsinki Heart Study. JAMA 1988, 260, 641. [Google Scholar] [CrossRef] [PubMed]
  6. Robins, S.; Collins, D.; Wittes, J. Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: A randomized controlled trial. ACC Curr. J. Rev. 2001, 10, 23–24. [Google Scholar] [CrossRef]
  7. Cuchel, M.; Rader, D. Macrophage Reverse Cholesterol Transport. Circulation 2006, 113, 2548–2555. [Google Scholar] [CrossRef]
  8. Zhong, S.; Sharp, D.S.; Grove, J.S.; Bruce, C.; Yano, K.; Curb, J.D.; Tall, A.R. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J. Clin. Investig. 1996, 97, 2917–2923. [Google Scholar] [CrossRef]
  9. Haase, C.L.; Tybjaerg-Hansen, A.; Grande, P.; Frikke-Schmidt, R. Genetically Elevated Apolipoprotein A-I, High-Density Lipoprotein Cholesterol Levels, and Risk of Ischemic Heart Disease. J. Clin. Endocrinol. Metab. 2010, 95, 500–510. [Google Scholar] [CrossRef]
  10. Voight, B.F.; Peloso, G.M.; Orho-Melander, M.; Frikke-Schmidt, R.; Barbalić, M.; Jensen, M.K.; Hindy, G.; Holm, H.; Ding, E.L.; Johnson, T.; et al. Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study. Lancet 2012, 380, 572–580. [Google Scholar] [CrossRef]
  11. Schwartz, G.G.; Olsson, A.G.; Abt, M.; Ballantyne, C.M.; Barter, P.J.; Brumm, J.; Chaitman, B.R.; Holme, I.; Kallend, D.; Leiter, L.A.; et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. New Engl. J. Med. 2012, 367, 2089–2099. [Google Scholar] [CrossRef] [PubMed]
  12. Barter, P.J.; Caulfield, M.J.; Eriksson, M.; Grundy, S.M.; Kastelein, J.J.; Komajda, M.; López-Sendón, J.; Mosca, L.; Tardif, J.-C.; Waters, D.D.; et al. Effects of Torcetrapib in Patients at High Risk for Coronary Events. New Engl. J. Med. 2007, 357, 2109–2122. [Google Scholar] [CrossRef] [PubMed]
  13. Boden, W.E.; Probstfield, J.L.; Anderson, T.; Chaitman, B.R.; Desvignes-Nickens, P.; Koprowicz, K.; McBride, R.; Teo, K.; Weintraub, W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 2011, 365, 2255–2267. [Google Scholar]
  14. Santander, N.G.; Contreras-Duarte, S.; Awad, M.F.; Lizama, C.; Passalacqua, I.; Rigotti, A.; Busso, D. Developmental abnormalities in mouse embryos lacking the HDL receptor SR-BI. Hum. Mol. Genet. 2013, 22, 2551. [Google Scholar] [CrossRef]
  15. Anonymous. The coronary drug project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. The coronary drug project research group. JAMA 1972, 220, 996–1008. [Google Scholar]
  16. Maclure, M. Demonstration of Deductive Meta-Analysis: Ethanol Intake and Risk of Myocardial Infarction. Epidemiol. Rev. 1993, 15, 328–351. [Google Scholar] [CrossRef]
  17. Gaziano, J.; Buring, J.E. Alcohol intake, lipids and risks of myocardial infarction. Ciba Foundation Symposium—Bilharziasis 1998, 216, 86–110. [Google Scholar] [CrossRef]
  18. Toth, P.P.; Barter, P.J.; Rosenson, R.S.; Boden, W.E.; Chapman, M.J.; Cuchel, M.; D’Agostino, R.B.; Davidson, M.H.; Davidson, W.S.; Heinecke, J.W.; et al. High-density lipoproteins: A consensus statement from the National Lipid Association. J. Clin. Lipidol. 2013, 7, 484–525. [Google Scholar] [CrossRef]
  19. Rosenson, R.S.; Brewer, H.B.; Davidson, W.S.; Fayad, Z.A.; Fuster, V.; Goldstein, J.; Hellerstein, M.; Jiang, X.-C.; Phillips, M.; Rader, D.J.; et al. Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation 2012, 125, 1905–1919. [Google Scholar] [CrossRef]
  20. Rosenson, R.S.; Brewer, H.B.; Ansell, B.J.; Barter, P.; Chapman, M.J.; Heinecke, J.W.; Kontush, A.; Tall, A.R.; Webb, N.R. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat. Rev. Cardiol. 2015, 13, 48–60. [Google Scholar] [CrossRef]
  21. Rohatgi, A.; Khera, A.; Berry, J.D.; Givens, E.G.; Ayers, C.R.; Wedin, K.E.; Neeland, I.J.; Yuhanna, I.S.; Rader, D.R.; De Lemos, J.A.; et al. HDL cholesterol efflux capacity and incident cardiovascular events. New Engl. J. Med. 2014, 371, 2383–2393. [Google Scholar] [CrossRef] [PubMed]
  22. Khera, A.V.; Cuchel, M.; De La Llera-Moya, M.; Rodrigues, A.; Burke, M.F.; Jafri, K.; French, B.C.; Phillips, J.A.; Mucksavage, M.L.; Wilensky, R.L.; et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. New Engl. J. Med. 2011, 364, 127–135. [Google Scholar] [CrossRef] [PubMed]
  23. Saleheen, D.; Scott, R.; Javad, S.; Zhao, W.; Rodrigues, A.; Picataggi, A.; Lukmanova, D.; Mucksavage, M.L.; Luben, R.N.; Billheimer, J.; et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: A prospective case-control study. Lancet Diabetes Endocrinol. 2015, 3, 507–513. [Google Scholar] [CrossRef]
  24. Soria-Florido, M.T.; Castañer, O.; Lassale, C.; Estruch, R.; Salas-Salvadó, J.; Martínez-González, M.Á.; Corella, D.; Ros, E.; Arós, F.; Elosua, R.; et al. Dysfunctional High-Density Lipoproteins Are Associated With a Greater Incidence of Acute Coronary Syndrome in a Population at High Cardiovascular Risk. Circulation 2020, 141, 444–453. [Google Scholar] [CrossRef]
  25. Swertfeger, D.; Rebholz, S.; Li, H.; Shah, A.S.; Davidson, W.S.; Lu, L.J. Feasibility of a plasma bioassay to assess oxidative protection of low-density lipoproteins by high-density lipoproteins. J. Clin. Lipidol. 2018, 12, 1539–1548. [Google Scholar] [CrossRef]
  26. Yvan-Charvet, L.; Wang, N.; Tall, A.R. Role of HDL, ABCA1, and ABCG1 Transporters in Cholesterol Efflux and Immune Responses. Arter. Thromb. Vasc. Boil. 2010, 30, 139–143. [Google Scholar] [CrossRef]
  27. Zimmer, S.; Grebe, A.; Bakke, S.S.; Bode, N.; Halvorsen, B.; Ulas, T.; Skjelland, M.; De Nardo, D.; Labzin, L.; Kerksiek, A.; et al. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci. Transl. Med. 2016, 8, 333ra50. [Google Scholar] [CrossRef]
  28. Li, Y.; Schwabe, R.F.; DeVries-Seimon, T.; Yao, P.M.; Gerbod-Giannone, M.-C.; Tall, A.R.; Davis, R.J.; Flavell, R.; Brenner, D.A.; Tabas, I. Free Cholesterol-loaded Macrophages Are an Abundant Source of Tumor Necrosis Factor-α and Interleukin-6. J. Boil. Chem. 2005, 280, 21763–21772. [Google Scholar] [CrossRef]
  29. Fotakis, P.; Kothari, V.; Thomas, D.G.; Westerterp, M.; Molusky, M.M.; Altin, E.; Abramowicz, S.; Wang, N.; He, Y.; Heinecke, J.W.; et al. Anti-Inflammatory Effects of HDL (High-Density Lipoprotein) in Macrophages Predominate Over Proinflammatory Effects in Atherosclerotic Plaques. Arter. Thromb. Vasc. Boil. 2019, 39, 253. [Google Scholar] [CrossRef]
  30. Tchoua, U.; Rosales, C.; Tang, D.; Gillard, B.K.; Vaughan, A.; Lin, H.Y.; Courtney, H.S.; Pownall, H.J. Serum Opacity Factor Enhances HDL-Mediated Cholesterol Efflux, Esterification and Anti Inflammatory Effects. Lipids 2010, 45, 1117–1126. [Google Scholar] [CrossRef]
  31. Ross, R.; A Glomset, J. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 1973, 180, 1332–1339. [Google Scholar] [CrossRef] [PubMed]
  32. Gillard, B.K.; Bassett, G.R.; Gotto, A.M.; Rosales, C.; Pownall, H.J. Scavenger receptor B1 (SR-B1) profoundly excludes high density lipoprotein (HDL) apolipoprotein AII as it nibbles HDL-cholesteryl ester. J. Boil. Chem. 2017, 292, 8864–8873. [Google Scholar] [CrossRef] [PubMed]
  33. Glass, C.; Pittman, R.C.; Weinstein, D.B.; Steinberg, D. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: Selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc. Natl. Acad. Sci. USA 1983, 80, 5435–5439. [Google Scholar] [CrossRef] [PubMed]
  34. Acton, S.; Rigotti, A.; Landschulz, K.T.; Xu, S.; Hobbs, H.H.; Krieger, M. Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor. Science 1996, 271, 518–520. [Google Scholar] [CrossRef]
  35. Smoak, K.A.; Aloor, J.J.; Madenspacher, J.; Merrick, B.A.; Collins, J.B.; Zhu, X.; Cavigiolio, G.; Oda, M.N.; Parks, J.S.; Fessler, M.B. Myeloid Differentiation Primary Response Protein 88 Couples Reverse Cholesterol Transport to Inflammation. Cell Metab. 2010, 11, 493–502. [Google Scholar] [CrossRef]
  36. Van der Vorst, E.P.C.; Theodorou, K.; Wu, Y.; Hoeksema, M.A.; Goossens, P.; Bursill, C.A.; Aliyev, T.; Huitema, L.F.A.; Tas, S.W.; Wolfs, I.M.J.; et al. High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling. Cell Metab. 2017, 25, 197–207. [Google Scholar] [CrossRef]
  37. Li, X.-M.; Tang, W.H.W.; Mosior, M.K.; Huang, Y.; Wu, Y.; Matter, W.; Gao, V.; Schmitt, D.; DiDonato, J.A.; Fisher, E.A.; et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arter. Thromb. Vasc. Boil. 2013, 33, 1696–1705. [Google Scholar] [CrossRef] [PubMed]
  38. Mutharasan, R.K.; Thaxton, C.S.; Berry, J.; Daviglus, M.L.; Yuan, C.; Sun, J.; Ayers, C.; Lloyd-Jones, D.; Wilkins, J.T. HDL efflux capacity, HDL particle size, and high-risk carotid atherosclerosis in a cohort of asymptomatic older adults: The Chicago Healthy Aging Study. J. Lipid Res. 2017, 58, 600–606. [Google Scholar] [CrossRef]
  39. Aeddula, N.R.; Trivedi, N.; Pathireddy, S.; De Vries, R.; Groen, A.K.; Dullaart, R.P.F.; Asleh, R.; Levy, A.P.; Blum, S.; Frohlich, J.; et al. Cholesterol Efflux Capacity and Atherosclerosis. New Engl. J. Med. 2011, 364, 1472–1475. [Google Scholar] [CrossRef]
  40. Josefs, T.; Wouters, K.; Tietge, U.J.; Annema, W.; Dullaart, R.P.; Vaisar, T.; Arts, I.C.; Van Der Kallen, C.J.; Stehouwer, C.D.; Schalkwijk, C.G.; et al. High-density lipoprotein cholesterol efflux capacity is not associated with atherosclerosis and prevalence of cardiovascular outcome: The CODAM study. J. Clin. Lipidol. 2020, 14, 122–132. [Google Scholar] [CrossRef] [PubMed]
  41. Brenn, T. The Tromso heart study: Alcoholic beverages and coronary risk factors. J. Epidemiol. Community Heal. 1986, 40, 249–256. [Google Scholar] [CrossRef] [PubMed]
  42. Cuvelier, I.; Steinmetz, J.; Mikstacki, T.; Siest, G. Variations in total phospholipids and high-density lipoprotein phospholipids in plasma from a general population: Reference intervals and influence of xenobiotics. Clin. Chem. 1985, 31, 763–766. [Google Scholar] [CrossRef]
  43. Clevidence, B.A.; Reichman, M.E.; Judd, J.T.; Muesing, R.A.; Schatzkin, A.; Schaefer, E.J.; Li, Z.; Jenner, J.; Brown, C.C.; Sunkin, M. Effects of alcohol consumption on lipoproteins of premenopausal women. A controlled diet study. Arter. Thromb. Vasc. Boil. 1995, 15, 179–184. [Google Scholar] [CrossRef] [PubMed]
  44. Hendriks, H.F.J.; Veenstra, J.; Van Tol, A.; Groener, J.E.M.; Schaafsma, G. Modearte Doses of Alcoholic Beverages with Dinner and Postprandial High Density Lipoprotein Composition. Alcohol Alcohol. 1998, 33, 403–410. [Google Scholar] [CrossRef] [PubMed]
  45. Baer, D.J.; Judd, J.T.; Clevidence, B.A.; Muesing, R.A.; Campbell, W.S.; Brown, E.D.; Taylor, P.R. Moderate alcohol consumption lowers risk factors for cardiovascular disease in postmenopausal women fed a controlled diet. Am. J. Clin. Nutr. 2002, 75, 593–599. [Google Scholar] [CrossRef]
  46. Hartung, G.H.; Lawrence, S.J.; Reeves, R.S.; Foreyt, J.P. Effect of alcohol and exercise on postprandial lipemia and triglyceride clearance in men. Atherosclerosis 1993, 100, 33–40. [Google Scholar] [CrossRef]
  47. Hartung, G.H.; Foreyt, J.P.; Mitchell, R.E.; Reeves, R.S.; Gotto, A.M. Effect of Alcohol Intake on High-Density Lipoprotein Cholesterol Levels in Runners and Inactive Men. JAMA 1983, 249, 747. [Google Scholar] [CrossRef]
  48. Kabagambe, E.K.; Baylin, A.; Ruiz-Narvaez, E.; Rimm, E.B.; Campos, H. Alcohol intake, drinking patterns, and risk of nonfatal acute myocardial infarction in Costa Rica. Am. J. Clin. Nutr. 2005, 82, 1336–1345. [Google Scholar] [CrossRef]
  49. Mukamal, K.J.; Jensen, M.K.; Grønbæk, M.; Stampfer, M.J.; Manson, J.E.; Pischon, T.; Rimm, E.B. Drinking Frequency, Mediating Biomarkers, and Risk of Myocardial Infarction in Women and Men. Circulation 2005, 112, 1406–1413. [Google Scholar] [CrossRef]
  50. Beulens, J.W.J.; Rimm, E.B.; Ascherio, A.; Spiegelman, N.; Hendriks, H.F.J.; Mukamal, K.J. Alcohol Consumption and Risk for Coronary Heart Disease among Men with Hypertension. Ann. Intern. Med. 2007, 146, 10. [Google Scholar] [CrossRef]
  51. Mukamal, K.J.; Chiuve, S.E.; Rimm, E.B. Alcohol Consumption and Risk for Coronary Heart Disease in Men with Healthy Lifestyles. Arch. Intern. Med. 2006, 166, 2145. [Google Scholar] [CrossRef] [PubMed]
  52. Yusuf, S.; Hawken, S.; Ounpuu, S.; Dans, T.; Avezum, A.; Lanas, F.; McQueen, M.; Budaj, A.; Pais, P.; Varigos, J.; et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): Case-control study. Lancet 2004, 364, 937–952. [Google Scholar] [CrossRef]
  53. Goldberg, I.J.; Mosca, L.; Piano, M.R.; Fisher, E.A. Wine and Your Heart. A Science Advisory for Healthcare Professionals from the Nutrition Committee, Council on Epidemiology and Prevention, and Council on Cardiovascular Nursing of the American Heart Association. Circulation 2001, 103, 472–475. [Google Scholar] [CrossRef] [PubMed]
  54. Linn, S.; Carroll, M.; Johnson, C.; Fulwood, R.; Kalsbeek, W.; Briefel, R. High-density lipoprotein cholesterol and alcohol consumption in US white and black adults: Data from NHANES II. Am. J. Public Heal. 1993, 83, 811–816. [Google Scholar] [CrossRef] [PubMed][Green Version]
  55. Silva, E.R.D.O.E.; Foster, D.; Harper, M.M.; Seidman, C.E.; Smith, J.D.; Breslow, J.L.; Brinton, E.A. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation 2000, 102, 2347–2352. [Google Scholar] [CrossRef]
  56. Thun, M.J.; Monaco, J.H.; Peto, R.; Heath, C.W.; Doll, R.; Lopez, A.; Henley, S.J. Alcohol Consumption and Mortality among Middle-Aged and Elderly U.S. Adults. New Engl. J. Med. 1997, 337, 1705–1714. [Google Scholar] [CrossRef]
  57. Gordon, T.; Kannel, W.B. Drinking and Mortality: The Framingham Study. Am. J. Epidemiology 1984, 120, 97–107. [Google Scholar] [CrossRef]
  58. Magnus, P.; Bakke, E.; Hoff, D.A.; Høiseth, G.; Graff-Iversen, S.; Knudsen, G.P.S.; Myhre, R.; Normann, P.T.; Næss, Ø.; Tambs, K.; et al. Controlling for High-Density Lipoprotein Cholesterol Does Not Affect the Magnitude of the Relationship Between Alcohol and Coronary Heart Disease. Circulation 2011, 124, 2296–2302. [Google Scholar] [CrossRef]
  59. Marques-Vidal, P.; Bochud, M.; Paccaud, F.; Waterworth, D.; Bergmann, S.; Preisig, M.; Waeber, G.; Vollenweider, P. No interaction between alcohol consumption and HDL-related genes on HDL cholesterol levels. Atherosclerosis 2010, 211, 551–557. [Google Scholar] [CrossRef]
  60. Baraona, E.; Lieber, C.S. Alcohol and lipids. Recent Dev. Alcohol. 1998, 14, 97–134. [Google Scholar]
  61. World Health Organization. United States of America, Alcohol Consumption. 2016. Available online: https://www.who.int/substance_abuse/publications/global_alcohol_report/profiles/usa.pdf (accessed on 26 June 2018).
  62. Eng, M.Y.; Luczak, S.E.; Wall, T.L. ALDH2, ADH1B, and ADH1C Genotypes in Asians: A Literature Review. Alcohol Res. Heal. J. Natl. Inst. Alcohol Abus. Alcohol. 2007, 30, 22–27. [Google Scholar]
  63. Ebtehaj, S.; Gruppen, E.G.; Bakker, S.J.; Dullaart, R.P.; Tietge, U.J. HDL (High-Density Lipoprotein) Cholesterol Efflux Capacity Is Associated With Incident Cardiovascular Disease in the General Population. Arter. Thromb. Vasc. Boil. 2019, 39, 1874–1883. [Google Scholar] [CrossRef] [PubMed]
  64. Khera, A.V.; Demler, O.V.; Adelman, S.J.; Collins, H.L.; Glynn, R.J.; Ridker, P.M.; Rader, D.J.; Mora, S. Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 2017, 135, 2494–2504. [Google Scholar] [CrossRef] [PubMed]
  65. Sierksma, A.; Vermunt, S.H.F.; Lankhuizen, I.M.; Van Der Gaag, M.S.; Scheek, L.M.; Grobbee, D.E.; Van Tol, A.; Hendriks, H.F. Effect of Moderate Alcohol Consumption on Parameters of Reverse Cholesterol Transport in Postmenopausal Women. Alcohol. Clin. Exp. Res. 2004, 28, 662–666. [Google Scholar] [CrossRef]
  66. Lesná, I.K.; Suchánek, P.; Stávek, P.; Poledne, R. May alcohol-induced increase of HDL be considered as atheroprotective? Physiol. Res. 2009, 59, 407–413. [Google Scholar]
  67. Van Der Gaag, M.S.; Van Tol, A.; Vermunt, S.H.; Scheek, L.M.; Schaafsma, G.; Hendriks, H.F. Alcohol consumption stimulates early steps in reverse cholesterol transport. J. Lipid Res. 2001, 42, 2077–2083. [Google Scholar]
  68. Perret, B.; Ruidavets, J.-B.; Vieu, C.; Jaspard, B.; Cambou, J.-P.; Tercé, F.; Collet, X. Alcohol consumption is associated with enrichment of high-density lipoprotein particles in polyunsaturated lipids and increased cholesterol esterification rate. Alcohol. Clin. Exp. Res. 2002, 26, 1134–1140. [Google Scholar] [CrossRef]
  69. Senault, C.; Betoulle, D.; Luc, G.; Hauw, P.; Rigaud, D.; Fumeron, F. Beneficial effects of a moderate consumption of red wine on cellular cholesterol efflux in young men. Nutr. Metab. Cardiovasc. Dis. 2000, 10, 63–69. [Google Scholar]
  70. Davidson, W.S.; Gillotte, K.L.; Lund-Katz, S.; Johnson, W.J.; Rothblat, G.H.; Phillips, M. The Effect of High Density Lipoprotein Phospholipid Acyl Chain Composition on the Efflux of Cellular Free Cholesterol. J. Boil. Chem. 1995, 270, 5882–5890. [Google Scholar] [CrossRef]
  71. Akopian, D.; Kawashima, R.L.; Medh, J. Phosphatidylcholine-Mediated Aqueous Diffusion of Cellular Cholesterol Down-Regulates the ABCA1 Transporter in Human Skin Fibroblasts. Int. J. Biochem. Res. Rev. 2015, 5, 214–224. [Google Scholar] [CrossRef]
  72. Tchoua, U.; Gillard, B.K.; Pownall, H.J. HDL superphospholipidation enhances key steps in reverse cholesterol transport. Atherosclerosis 2009, 209, 430–435. [Google Scholar] [CrossRef] [PubMed]
  73. Gillotte, K.L.; Davidson, W.S.; Lund-Katz, S.; Rothblat, G.H.; Phillips, M.C. Removal of cellular cholesterol by pre-beta-HDL involves plasma membrane microsolubilization. J. Lipid Res. 1998, 39, 1918–1928. [Google Scholar] [PubMed]
  74. Beulens, J.W.; Sierksma, A.; Van Tol, A.; Van Gent, T.; Fournier, N.; Paul, J.-L.; Hendriks, H.F. Moderate Alcohol Consumption Increases Cholesterol Reflux mediated by ABCA1. Alcohol. Clin. Exp. Res. 2004, 28, 7. [Google Scholar] [CrossRef]
  75. Chung, B.-H.; Franklin, F.; Cho, B.H.S.; Segrest, J.P.; Hart, K.; Darnell, B.E. Potencies of Lipoproteins in Fasting and Postprandial Plasma to Accept Additional Cholesterol Molecules Released From Cell Membranes. Arter. Thromb. Vasc. Boil. 1998, 18, 1217–1230. [Google Scholar] [CrossRef] [PubMed]
  76. Wilson, D.E.; Schreibman, P.H.; Brewster, A.C.; Arky, R.A. The enhancement of alimentary lipemia by ethanol in man. J. Lab. Clin. Med. 1970, 75, 264–274. [Google Scholar] [PubMed]
  77. Pownall, H.J. Dietary ethanol is associated with reduced lipolysis of intestinally derived lipoproteins. J. Lipid Res. 1994, 35, 2105–2113. [Google Scholar] [PubMed]
  78. Julia, Z.; Duchene, E.; Fournier, N.; Bellanger, N.; Chapman, M.J.; Le Goff, W.; Guerin, M. Postprandial lipemia enhances the capacity of large HDL2 particles to mediate free cholesterol efflux via SR-BI and ABCG1 pathways in type IIB hyperlipidemia. J. Lipid Res. 2010, 51, 3350–3358. [Google Scholar] [CrossRef]
  79. Berryman, C.E.; Grieger, J.A.; West, S.G.; Chen, C.-Y.O.; Blumberg, J.B.; Rothblat, G.H.; Sankaranarayanan, S.; Kris-Etherton, P.M. Acute consumption of walnuts and walnut components differentially affect postprandial lipemia, endothelial function, oxidative stress, and cholesterol efflux in humans with mild hypercholesterolemia. J. Nutr. 2013, 143, 788–794. [Google Scholar] [CrossRef]
  80. Vasudevan, M.; Tchoua, U.; Gillard, B.K.; Jones, P.H.; Ballantyne, C.M.; Pownall, H.J. Modest diet-induced weight loss reduces macrophage cholesterol efflux to plasma of patients with metabolic syndrome. J. Clin. Lipidol. 2013, 7, 661–670. [Google Scholar] [CrossRef]
  81. Van Tol, A.; Groener, J.E.M.; Scheek, L.M.; Van Gent, T.; Veenstra, J.; Van De Pol, H.; Hendriks, H.F.J.; Schaafsma, G. Induction of net mass lipid transfer reactions in plasma by wine consumption with dinner. Eur. J. Clin. Investig. 1995, 25, 390–395. [Google Scholar] [CrossRef]
  82. Gaubatz, J.W.; Gillard, B.K.; Rosales, C.; Pownall, H.J. Dietary Alcohol and Fat Differentially Affect Plasma Cholesteryl Ester Transfer Activity and Triglycerides in Normo- and Hypertriglyceridemic Subjects. Lipids 2020. [Google Scholar] [CrossRef] [PubMed]
  83. Hayashi, S.; Watanabe, J.; Kawajiri, K. Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J. Biochem. 1991, 110, 559–565. [Google Scholar] [CrossRef] [PubMed]
  84. Rimm, E.B.; Klatsky, A.; Grobbee, D.; Stampfer, M.J. Review of moderate alcohol consumption and reduced risk of coronary heart disease: Is the effect due to beer, wine, or spirits? BMJ 1996, 312, 731–736. [Google Scholar] [CrossRef]
  85. Barefoot, J.C.; Grønbæk, M.; Feaganes, J.R.; McPherson, R.S.; Williams, R.; Siegler, I.C. Alcoholic beverage preference, diet, and health habits in the UNC Alumni Heart Study. Am. J. Clin. Nutr. 2002, 76, 466–472. [Google Scholar] [CrossRef] [PubMed]
  86. Pownall, H.J.; Ballantyne, C.M.; Kimball, K.T.; Simpson, S.L.; Yeshurun, D.; Gotto, A.M. Effect of moderate alcohol consumption on hypertriglyceridemia: A study in the fasting state. Arch. Intern. Med. 1999, 159, 981–987. [Google Scholar] [CrossRef] [PubMed]
  87. Sugiyama, S.; Fushimi, T.; Kishi, M.; Irie, S.; Tsuji, S.; Hosokawa, N.; Kaga, T. Bioavailability of acetate from two vinegar supplements: Capsule and drink. J. Nutr. Sci. Vitaminol. 2010, 56, 266–269. [Google Scholar] [CrossRef][Green Version]
  88. Nilsson, N.O.; Belfrage, P. Effects of acetate, acetaldehyde, and ethanol on lipolysis in isolated rat adipocytes. J. Lipid Res. 1978, 19, 737–741. [Google Scholar]
  89. Nilsson, N.E.; Kotarsky, K.; Owman, C.; Olde, B. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 2003, 303, 1047–1052. [Google Scholar] [CrossRef]
  90. Hong, Y.-H.; Nishimura, Y.; Hishikawa, D.; Tsuzuki, H.; Miyahara, H.; Gotoh, C.; Choi, K.-C.; Feng, D.D.; Chen, C.; Lee, H.-G.; et al. Acetate and Propionate Short Chain Fatty Acids Stimulate Adipogenesis via GPCR43. Endocrinology 2005, 146, 5092–5099. [Google Scholar] [CrossRef]
  91. Ge, H.; Li, X.; Weiszmann, J.; Wang, P.; Baribault, H.; Chen, J.-L.; Tian, H.; Li, Y. Activation of G Protein-Coupled Receptor 43 in Adipocytes Leads to Inhibition of Lipolysis and Suppression of Plasma Free Fatty Acids. Endocrinology 2008, 149, 4519–4526. [Google Scholar] [CrossRef]
  92. Abramson, E.A.; Arky, R.A. Acute antilipolytic effects of ethyl alcohol and acetate in man. J. Lab. Clin. Med. 1968, 72, 105–117. [Google Scholar] [PubMed]
  93. Pownall, H.J.; Brauchi, D.; Kilinç, C.; Osmundsen, K.; Pao, Q.; Payton-Ross, C.; Gotto, A.M.; Ballantyne, C.M. Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins. Atherosclerosis 1999, 143, 285–297. [Google Scholar] [CrossRef]
  94. Balasubramanyam, A.; Sekhar, R.V.; Jahoor, F.; Jones, P.H.; Pownall, H.J. Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: A model of ‘systemic steatosis’. Curr. Opin. Lipidol. 2004, 15, 59–67. [Google Scholar] [CrossRef] [PubMed]
  95. Hlebowicz, J.; Darwich, G.; Björgell, O.; Almér, L.-O. Effect of apple cider vinegar on delayed gastric emptying in patients with type 1 diabetes mellitus: A pilot study. BMC Gastroenterol. 2007, 7, 46. [Google Scholar] [CrossRef] [PubMed]
  96. Johnston, C.S.; Kim, C.M.; Buller, A.J. Vinegar improves insulin sensitivity to a high-carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care 2004, 27, 281–282. [Google Scholar] [CrossRef] [PubMed]
  97. Johnston, C.S.; White, A.M.; Kent, S.M. Preliminary evidence that regular vinegar ingestion favorably influences hemoglobin A1c values in individuals with type 2 diabetes mellitus. Diabetes Res. Clin. Pr. 2009, 84, e15–e17. [Google Scholar] [CrossRef]
  98. Liatis, S.; Grammatikou, S.; Poulia, K.A.; Perrea, D.; Makrilakis, K.; Diakoumopoulou, E.; Katsilambros, N. Vinegar reduces postprandial hyperglycaemia in patients with type II diabetes when added to a high, but not to a low, glycaemic index meal. Eur. J. Clin. Nutr. 2010, 64, 727–732. [Google Scholar] [CrossRef]
  99. Balliett, M.; Burke, J.R. Changes in anthropometric measurements, body composition, blood pressure, lipid profile, and testosterone in patients participating in a low-energy dietary intervention. J. Chiropr. Med. 2013, 12, 3–14. [Google Scholar] [CrossRef]
  100. Shishehbor, F.; Mansoori, A.; Sarkaki, A.R.; Jalali, M.T.; Latifi, S.M. Apple Cider Vinegar Attenuates Lipid Profile in Normal and Diabetic Rats. Pak. J. Boil. Sci. 2008, 11, 2634–2638. [Google Scholar] [CrossRef]
  101. Jasbi, P.; Baker, O.; Shi, X.; Gonzalez, L.A.; Wang, S.; Anderson, S.; Xi, B.; Gu, H.; Johnston, C.S. Daily red wine vinegar ingestion for eight weeks improves glucose homeostasis and affects the metabolome but does not reduce adiposity in adults. Food Funct. 2019, 10, 7343–7355. [Google Scholar] [CrossRef]
  102. Mitrou, P.; Petsiou, E.; Papakonstantinou, E.; Maratou, E.; Lambadiari, V.; Dimitriadis, P.; Spanoudi, F.; A Raptis, S.; Dimitriadis, G. The role of acetic acid on glucose uptake and blood flow rates in the skeletal muscle in humans with impaired glucose tolerance. Eur. J. Clin. Nutr. 2015, 69, 734–739. [Google Scholar] [CrossRef] [PubMed]
  103. Johnston, C.S.; Steplewska, I.; Long, C.A.; Harris, L.N.; Ryals, R.H. Examination of the Antiglycemic Properties of Vinegar in Healthy Adults. Ann. Nutr. Metab. 2010, 56, 74–79. [Google Scholar] [CrossRef] [PubMed]
  104. Bouderbala, H.; Kaddouri, H.; Maharrar, M.; Kheroua, O.; Saidi, D. P2-11: Anti obesogenic effects of apple cider vinegar in rats subjected to a high fat diet. Annales de Cardiologie et d’Angéiologie 2015, 64, S27. [Google Scholar] [CrossRef]
  105. Fushimi, T.; Suruga, K.; Oshima, Y.; Fukiharu, M.; Tsukamoto, Y.; Goda, T. Dietary acetic acid reduces serum cholesterol and triacylglycerols in rats fed a cholesterol-rich diet. Br. J. Nutr. 2006, 95, 916–924. [Google Scholar] [CrossRef] [PubMed]
  106. Johnston, C.S.; Gaas, C.A. Vinegar: Medicinal Uses and Antiglycemic Effect. MedGenMed Medscape Gen. Med. 2006, 8, 61. [Google Scholar]
  107. Halima, B.H.; Sonia, G.; Sarra, K.; Houda, B.J.; Fethi, B.S.; Abdallah, A. Apple Cider Vinegar Attenuates Oxidative Stress and Reduces the Risk of Obesity in High-Fat-Fed Male Wistar Rats. J. Med. Food 2018, 21, 70–80. [Google Scholar] [CrossRef]
  108. Pingitore, A.; Gonzalez-Abuin, N.; Ruz-Maldonado, I.; Huang, G.C.; Frost, G.; Persaud, S.J. Short chain fatty acids stimulate insulin secretion and reduce apoptosis in mouse and human islets in vitro: Role of free fatty acid receptor 2. Diabetes, Obes. Metab. 2018, 21, 330–339. [Google Scholar] [CrossRef]
  109. Pomare, E.W.; Branch, W.J.; Cummings, J.H. Carbohydrate fermentation in the human colon and its relation to acetate concentrations in venous blood. J. Clin. Investig. 1985, 75, 1448–1454. [Google Scholar] [CrossRef]
  110. Topping, D.L.; Clifton, P.M. Short-chain fatty acids and human colonic function: Roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 2001, 81, 1031–1064. [Google Scholar] [CrossRef]
  111. Frost, G.; Sleeth, M.L.; Sahuri-Arisoylu, M.; Lizarbe, B.; Cerdan, S.; Brody, L.; Anastasovska, J.; Ghourab, S.; Hankir, M.; Zhang, S.; et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 2014, 5, 3611. [Google Scholar] [CrossRef]
  112. Lundquist, F.; Tygstrup, N.; Winkler, K.; Mellemgaard, K.; Munck-Petersen, S. Etanol Metabolism and Production of Free Acetate in the Human Liver. J. Clin. Investig. 1962, 41, 955–961. [Google Scholar] [CrossRef] [PubMed]
  113. Siler, S.Q.; Neese, R.A.; Hellerstein, M.K. De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption. Am. J. Clin. Nutr. 1999, 70, 928–936. [Google Scholar] [CrossRef] [PubMed]
  114. Liljeberg, H.; Björck, I. Delayed gastric emptying rate may explain improved glycaemia in healthy subjects to a starchy meal with added vinegar. Eur. J. Clin. Nutr. 1998, 52, 368–371. [Google Scholar] [CrossRef] [PubMed]
  115. Leeman, M.; Ostman, E.; Björck, I. Vinegar dressing and cold storage of potatoes lowers postprandial glycaemic and insulinaemic responses in healthy subjects. Eur. J. Clin. Nutr. 2005, 59, 1266–1271. [Google Scholar] [CrossRef]
  116. Sugiyama, M.; Tang, A.C.; Wakaki, Y.; Koyama, W. Glycemic index of single and mixed meal foods among common Japanese foods with white rice as a reference food. Eur. J. Clin. Nutr. 2003, 57, 743–752. [Google Scholar] [CrossRef]
  117. Ostman, E.; Elmståhl, H.G.L.; Björck, I.M.E. Inconsistency between glycemic and insulinemic responses to regular and fermented milk products. Am. J. Clin. Nutr. 2001, 74, 96–100. [Google Scholar] [CrossRef]
  118. Vu, C.N.; Ruiz-Esponda, R.; Yang, E.Y.; Chang, E.; Gillard, B.K.; Pownall, H.J.; Hoogeveen, R.; Coraza, I.; Balasubramanyam, A. Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV/HAART-associated dyslipidemia: Further evidence for a unique form of Metabolic Syndrome in HIV patients. Metabolism 2013, 62, 1014–1020. [Google Scholar] [CrossRef]
Biomolecules 10 00987 g001
Figure 1. Traditional reverse cholesterol transport (RCT) model in the context of athero-protection. Nascent high-density lipoproteins (nHDL), apolipoprotein A1 (APOA1), adenosine triphosphate (ATP) binding cassette transporter subfamily A member 1 (ABCA1), free cholesterol (FC), lecithin:cholesterol acyltransferase (LCAT), scavenger receptor class B member 1 (SCARB1).
Figure 1. Traditional reverse cholesterol transport (RCT) model in the context of athero-protection. Nascent high-density lipoproteins (nHDL), apolipoprotein A1 (APOA1), adenosine triphosphate (ATP) binding cassette transporter subfamily A member 1 (ABCA1), free cholesterol (FC), lecithin:cholesterol acyltransferase (LCAT), scavenger receptor class B member 1 (SCARB1).
Biomolecules 10 00987 g001
Biomolecules 10 00987 g002
Figure 2. Plasma analytes among normotriglyceridemic (NTG) and hypertriglyceridemic (HTG) subjects after consuming 400 mL of 10% ethanol. (A) Ethanol concentrations, (B) Triglyceride (TG) concentration, and (C) % baseline triglyceride (TG); 6-h increases vs. baseline = 3% (HTG, p = 0.16) and 53% (NTG, p = 0.002). With permission [86].
Figure 2. Plasma analytes among normotriglyceridemic (NTG) and hypertriglyceridemic (HTG) subjects after consuming 400 mL of 10% ethanol. (A) Ethanol concentrations, (B) Triglyceride (TG) concentration, and (C) % baseline triglyceride (TG); 6-h increases vs. baseline = 3% (HTG, p = 0.16) and 53% (NTG, p = 0.002). With permission [86].
Biomolecules 10 00987 g002
Biomolecules 10 00987 g003
Figure 3. Plasma NEFA and acetate levels vs. time among HTG and NTG. Values are mean ± standard error of the mean (SEM). In both groups, the acetate concentration at which lipolysis recovers, according to increasing non-esterified fatty acid (NEFA) concentration, is ~0.2 mM acetate. With permission [86].
Figure 3. Plasma NEFA and acetate levels vs. time among HTG and NTG. Values are mean ± standard error of the mean (SEM). In both groups, the acetate concentration at which lipolysis recovers, according to increasing non-esterified fatty acid (NEFA) concentration, is ~0.2 mM acetate. With permission [86].
Biomolecules 10 00987 g003
Biomolecules 10 00987 g004
Figure 4. Mechanistic model for acetate-mediated alteration of the plasma lipoprotein profile (see text for details). Adipose tissue (AT), very-low-density lipoproteins (VLDL), cholesteryl ester transfer protein (CETP), cholesteryl ester (CE), non-esterified fatty acids (NEFA), high-density lipoproteins (HDL), triglycerides (TG), scavenger receptor class B member 1 (SCARB1).
Figure 4. Mechanistic model for acetate-mediated alteration of the plasma lipoprotein profile (see text for details). Adipose tissue (AT), very-low-density lipoproteins (VLDL), cholesteryl ester transfer protein (CETP), cholesteryl ester (CE), non-esterified fatty acids (NEFA), high-density lipoproteins (HDL), triglycerides (TG), scavenger receptor class B member 1 (SCARB1).
Biomolecules 10 00987 g004
Biomolecules 10 00987 g005
Figure 5. Schematic model of the conversion of dietary components into acetate, the bioactive ligand for free fatty acid receptor 2 (FFAR2).
Figure 5. Schematic model of the conversion of dietary components into acetate, the bioactive ligand for free fatty acid receptor 2 (FFAR2).
Biomolecules 10 00987 g005

Share and Cite

MDPI and ACS Style

Rosales, C.; Gillard, B.K.; Gotto, A.M., Jr.; Pownall, H.J. The Alcohol–High-Density Lipoprotein Athero-Protective Axis. Biomolecules 2020, 10, 987. https://doi.org/10.3390/biom10070987

AMA Style

Rosales C, Gillard BK, Gotto AM Jr., Pownall HJ. The Alcohol–High-Density Lipoprotein Athero-Protective Axis. Biomolecules. 2020; 10(7):987. https://doi.org/10.3390/biom10070987

Chicago/Turabian Style

Rosales, Corina, Baiba K. Gillard, Antonio M. Gotto, Jr., and Henry J. Pownall. 2020. "The Alcohol–High-Density Lipoprotein Athero-Protective Axis" Biomolecules 10, no. 7: 987. https://doi.org/10.3390/biom10070987

APA Style

Rosales, C., Gillard, B. K., Gotto, A. M., Jr., & Pownall, H. J. (2020). The Alcohol–High-Density Lipoprotein Athero-Protective Axis. Biomolecules, 10(7), 987. https://doi.org/10.3390/biom10070987

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop