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. Author manuscript; available in PMC: 2024 Sep 1.
Published in final edited form as: J Clin Lipidol. 2023 Jul 28;17(5):577–586. doi: 10.1016/j.jacl.2023.07.005

Diet-Derived and Diet-Related Endogenously Produced Palmitic Acid: Effects on Metabolic Regulation and Cardiovascular Disease Risk

Carmen E Annevelink 1,1, Philip A Sapp 1,1, Kristina S Petersen 1, Greg C Shearer 1, Penny M Kris-Etherton 1,2
PMCID: PMC10822025  NIHMSID: NIHMS1929134  PMID: 37666689

Abstract

Palmitic acid is the predominant dietary saturated fatty acid (SFA) in the US diet. Plasma palmitic acid is derived from dietary fat and also endogenously from de novo lipogenesis (DNL) and lipolysis. DNL is affected by excess energy intake resulting in overweight and obesity, and the macronutrient profile of the diet. A low-fat diet (higher carbohydrate and/or protein) promotes palmitic acid synthesis in adipocytes and the liver. A high-fat diet is another source of palmitic acid that is taken up by adipose tissue, liver, heart and skeletal muscle via lipolytic mechanisms. Moreover, overweight/obesity and accompanying insulin resistance increase non-esterified fatty acid (NEFA) production. Palmitic acid may affect cardiovascular disease (CVD) risk via mechanisms beyond increasing LDL-C, notably synthesis of ceramides and possibly through branched fatty acid esters of hydroxy fatty acids (FAHFAs) from palmitic acid. Ceramides are positively associated with incident CVD, whereas the role of FAHFAs is uncertain. Given the new evidence about dietary regulation of palmitic acid metabolism there is interest in learning more about how diet modulates circulating palmitic acid concentrations and, hence, potentially CVD risk. This is important because of the heightened interest in low carbohydrate (carbohydrate controlled) and high carbohydrate (low-fat) diets coupled with the ongoing overweight/obesity epidemic, all of which can increase plasma palmitic acid levels by different mechanisms. Consequently, learning more about palmitic acid biochemistry, trafficking and how its metabolites affect CVD risk will inform future dietary guidance to further lower the burden of CVD.

Keywords: Palmitic acid, diet-derived, endogenous synthesis, ceramides, CVD risk, FAHFAs

Introduction

The relationships between intake and tissue levels of saturated fatty acids (SFAs) and cardiovascular disease (CVD) risk have been extensively studied over the past six decades. Individual SFAs differ in their metabolic effects. Palmitic acid (C16:0), a long chain fatty acid (FA), is the most abundant SFA in the U.S. diet representing about 55% of dietary SFAs [1], and comprises about 20-30% of all FA in membrane phospholipids (PL) and triglycerides (TG) [2]. Palmitic acid is derived from the diet or by endogenous synthesis (i.e., de novo lipogenesis (DNL)) from excess energy intake from carbohydrates and/or protein. Clinical and observational evidence indicates that palmitic acid from both exogenous and endogenous sources is adversely associated with CVD risk, as well as total mortality [3-8]. It is well established that dietary palmitic acid increases low-density lipoprotein cholesterol (LDL-C) [9], however, palmitic acid also likely increases CVD risk via other mechanisms. Emerging evidence suggests that palmitic acid increases ceramides, which may increase CVD risk. The epidemiological and clinical trial evidence provides insights into the molecular mechanisms that explain how SFAs increase CVD risk, particularly the contribution of palmitic acid to insulin resistance and the subsequent metabolic sequelae, including hepatic steatosis, as well as endothelial dysfunction. However, there is still a gap in our understanding of the relationship between dietary palmitic acid, circulating palmitic acid, and CVD risk. The aim of this review is to summarize the evidence that supports a role of exogenous and endogenously produced palmitic acid in the development of CVD. We will summarize: 1) the relationship between palmitic acid and cardiometabolic risks; 2) dietary modulation of circulating palmitic acid concentrations; 3) palmitic acid biochemistry, trafficking and its metabolites; and 4) evidence gaps and future directions for advancing this research area.

Dietary and circulating palmitic acid and CVD risk

Dietary palmitic acid and CVD risk

There is evidence of an association between individual SFAs and CVD risk. Two prospective cohort studies including 115,782 men and women showed increased hazard ratios (HR) for coronary heart disease (CHD) with comparing extreme quintiles of intake for myristic acid (HR: 1.13 [95% CI 1.05, 1.22]), palmitic acid (1.18 [1.09, 1.27]), and stearic acid (1.18 [1.09, 1.28]) [10]. In substitution analyses, each 1% replacement of palmitic acid with polyunsaturated fatty acids (PUFA) (HR: 0.88 [95% CI 0.81, 0.96]), whole grain carbohydrates (0.90 [0.83, 0.97]), or plant proteins (0.89 [0.82, 0.97]) was associated with lower CHD risk; replacement of lauric, myristic and stearic acid with PUFA, whole grains or plant protein was not associated with CHD risk reduction. A systematic review and meta-regression of clinical trials demonstrated that a 1% replacement of energy from carbohydrates with palmitic acid increased total cholesterol (1.59 mg/dL), LDL-C (1.39 mg/dL), high-density lipoprotein cholesterol (HDL-C) (0.39 mg/dL), and decreased TG (−0.97 mg/dL) [11].

Circulating palmitic acid and CVD risk

Studies evaluating circulating palmitic acid and CVD risk factors, heart failure, and incident type 2 diabetes mellitus (T2DM) have reported varying results that differ based on the population studied. A cross-sectional analysis of circulating FA levels and metabolic risk factors in 172 healthy, normal weight (BMI: 22.6 ± 3.5), adults showed that total SFA concentrations were significantly positively correlated with waist circumference, TG, LDL-C, total cholesterol, systolic blood pressure, and diastolic blood pressure [12]. Interestingly, circulating palmitic acid was not significantly associated with any metabolic risk factors. However, studies in at-risk populations tend to report opposite results. In a prospective analysis conducted in a subsample (91 adults at high risk for developing CVD) of the PREDIMED cohort, a direct positive relationship was observed between one-year changes in palmitic acid and interleukin-6 (0.50 pg/mL [95% CI: 0.23, 0.77] per 1-SD increase) [4]. This study suggests there may be a relationship between increases in circulating palmitic acid and inflammation, but additional clinical trials are needed. An analysis of the Cardiovascular Health Study (n=4,249; mean age: 75.6y) demonstrated that higher plasma PL palmitic acid concentrations and increases in plasma palmitic acid concentrations (measured at baseline, 6, and 13 years) over the 22.1-year follow-up were positively associated with incident heart failure (interquartile HR: 1.17 [95% CI 1.00, 1.36] and 1.26 [95% CI 1.03, 1.55], respectively) [6]. Reduced membrane fluidity and impaired energy production observed with higher concentrations of palmitic acid (discussed in the biochemistry section [13]) may provide mechanistic insight to the relationship between palmitic acid concentrations and heart failure. In the Ludwigshafen Risk and Cardiovascular Health Study conducted with patients (n = 3259) referred for coronary angiography, an increase of 1-standard deviation in red blood cell palmitic acid was associated with an increased risk for all-cause mortality (HR: 1.08 (95% CI: 1.01-1.16) [5]. Moreover, in an analysis of 17 cohorts (mean baseline age 52.3 to 76.0y) from 12 countries including 65,255 adults free of T2DM at baseline, a higher risk of incident T2DM was observed for those in the highest vs. lowest quintile for palmitic acid concentrations (relative risk 1.53; 95% CI: 1.41, 1.66) [14]. Importantly, these studies that demonstrated significant associations between circulating palmitic acid and CVD risk, heart failure, total mortality and T2DM enrolled older and at-risk populations. Studies assessing healthy populations are limited. Further research is necessary to clarify the relationship between circulating palmitic acid and CVD risk.

Palmitic acid metabolites and CVD risk

Ceramides and branched fatty acid esters of hydroxy fatty acids (FAHFAs), synthesized from palmitic acid, have garnered interest because of their potential relationship with CVD risk. Two recent reviews concluded that ceramides, which are involved in endothelial dysfunction, predict cardiovascular events independent of other risk factors, and that reducing ceramide concentrations may decrease CVD risk [15, 16]. A case-control study including 1017 participants (n=230 CVD [cases] and n=787 randomly selected participants at baseline [controls]) from the PREDIMED trial showed a significant positive association between incident CVD and plasma ceramides (highest vs. lowest quartiles HR: 2.18 [95% CI: 1.36, 3.49]) [17]. An analysis of the Cardiovascular Health Study (n = 4206 individuals free from atrial fibrillation (AF) at baseline and 1198 cases identified over an 8.7-year median follow-up) demonstrated that ceramides and sphingomyelins with palmitic acid were associated with increased AF risk (HR: 1.31 [95% CI 1.03, 1.66] and 1.73 [95% CI 1.18, 2.55, respectively]). In contrast, ceramides and sphingomyelins with other long-chain SFAs were associated with a reduced risk of AF (HR: 0.71 [95% CI 0.59, 0.86] and 0.6 [95% CI 0.46, 0.77], respectively) [18]. Several scoring techniques have been developed to assess the relationship between ceramides and cardiovascular events: cardiac event risk test 1 (CERT1) based on ceramides and cardiac event risk test 2 (CERT2) based on ceramides and phosphatidylcholines [19]. A recent systematic review and meta-analysis assessing CERT2 scores stratified into quartiles and major adverse cardiovascular events (MACE: stroke, myocardial infarction, or cardiovascular death) in 26,896 adults with established coronary artery disease demonstrated that individuals with a CERT2 score of 9-12 (n=4,438), 7-8 (n=6,710), and 4-6 (n=11,341) had 165, 81 and 35% (RR=2.65 [95% CI: 1.85, 3.80], 1.81 [1.40, 2.34], and 1.35 [1.11, 1.64], respectively) increased risk for MACE compared to those with a CERT2 score of 0-3 (n=4,407) [20]. Poss et al. [21] developed a machine learning derived scoring technique (sphingolipid-inclusive CAD risk score [SIC]) using ceramide concentrations (32 different sphingolipids) from 462 patients with CAD and 212 controls that more accurately categorized individuals with CAD than classic CVD risk factors (e.g., TG, LDL-C, and CERT1). One crossover clinical trial of 46 adults with rheumatoid arthritis assessed the effects of a Mediterranean diet vs. a Western-style control diet for 10-weeks with a 4-month washout period and demonstrated no significant differences in CERT2 scores but several individual components were significantly lower for the Mediterranean compared to Western-style diet. Preliminary evidence from murine studies suggests that FAHFAs may improve glucose tolerance and insulin secretion [22]. However, these results have not been replicated and studies in humans are limited. Therefore, further research is necessary to understand how higher circulating palmitic acid (diet and DNL derived) impacts individual ceramides/FAHFAs, ceramide-based risk scores (CERT1 and CERT2), and the implications for cardiometabolic disease risk.

Effect of diet on circulating palmitic acid

SFA in the diet

The 2020-2025 Dietary Guidelines for Americans recommend that SFAs provide <10% of total energy, which is based on strong evidence demonstrating reductions in LDL-C when SFAs are replaced with unsaturated FA [23]. Furthermore, replacing SFAs with PUFAs reduces risk of coronary artery disease (CAD) and CVD mortality. The 2015-2016 National Health and Nutrition Examination Survey (NHANES) reported that mean SFAs intake was approximately 12% of total energy with 87% of males and 88% of females exceeding the 2020-2025 Dietary Guidelines for Americans recommendation [24]. Dietary guidelines focus on total SFAs rather than individual FAs. Based on 2017-2020 NHANES data, palmitic acid consumption is approximately 15.6 g/d (6.5% of total energy) for individuals 20 years and older [1]. Similarly, a mean palmitic acid intake of 5.7% of total energy was observed in the Nurses’ Health Study (1984-2012) and Health Professionals Follow-Up Study (1986-2010) [10].

Palmitic acid from high-fat, high palmitic acid, diets

Studies assessing the effects of dietary palmitic acid on tissue palmitic acid content and circulating concentrations are limited. We are aware of only one study that assessed the effect of a high palmitic acid diet, compared to other FA, on circulating palmitic acid under eucaloric conditions [3]. Denke and Grundy showed that a high palmitic acid diet (total fat 40% kcal; palmitic acid 43.4% of fat) increased the palmitic acid content in plasma TG by 32.1% after three weeks in 14 healthy men. The palmitic acid content of plasma TGs was significantly increased compared to isocaloric diets higher in lauric acid (23.2% increase; total fat 40% kcal; LA 43.9% of fat;) and oleic acid (21.7% increase; total fat 40% kcal; OA 75.8% of total fat). Total cholesterol and LDL-C were significantly increased following the palmitic acid diet compared to the lauric acid and oleic acid diets. Further studies examining how dietary palmitic acid modulates plasma and tissue levels are needed to advance our understanding of the in vivo metabolism of palmitic acid.

Under conditions of positive energy balance, increases in circulating palmitic acid have been observed with dietary intake of palmitic acid. Risérus and colleagues conducted a double-blind, seven week parallel study [25] and reported that overfeeding healthy adults with SFA enriched muffins (51% fat from palm oil [47.5% palmitic acid]), compared to PUFA enriched muffins (sunflower oil [6.2% palmitic acid]), significantly increased palmitic acid in cholesterol esters (mean difference: 1.2%; 95% CI: 0.83, 1.61) and subcutaneous adipose tissue TG (2.3%; 95% CI: 1.6, 2.9). Both diets induced weight gain (3% of initial weight), and adversely affected insulin sensitivity (increased insulin, HOMA-IR, and adiponectin). The SFA condition significantly increased visceral fat and total body fat compared to the PUFA condition. In a similar follow-up parallel trial conducted in adults with overweight and obesity [7], overfeeding with the SFA-enriched muffins increased palmitic acid concentrations in plasma PL and subcutaneous adipose tissue compared to sunflower oil enriched muffins (p<0.0001) after eight weeks. Despite similar weight gain following the diets, liver fat increased by approximately 53% following the SFA diet compared to a 2% decrease following the PUFA diet. Total cholesterol, LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, and apolipoprotein B (apoB) were increased following the SFA diet compared to the PUFA diet. Total ceramides increased following overfeeding with SFA, while overfeeding with PUFA decreased ceramides. Lastly, changes in serum ceramides were strongly associated with changes in pancreatic palmitic acid uptake; further research is needed to understand the impact of this. Dietary palmitate, from either eucaloric or hypercaloric diets, may induce changes in circulating palmitic acid and lipids/lipoproteins but only studies inducing weight gain have assessed ceramides and metabolic dysfunction (See Figure 1).

Figure 1.

Figure 1.

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Proposed Mechanisms by which Circulating Palmitic Acid from Diet-Derived and Diet-Related Endogenously Produced Palmitic Acid Modulate Metabolic Events that may Promote Atherosclerosis. Chronic energy surplus is associated with increased weight, increased liver fat, and insulin resistance. In this context, increased carbohydrate intake drives increased de novo lipogenesis (DNL) in the liver and increased fat intake (specifically from saturated fatty acids (SFA)) drives increased intracellular lipolysis in the adipose tissue. Overfeeding with SFA leads to increased palmitic acid-derived ceramides, but subsequent markers of inflammation or oxidative stress have not been consistently measured in overfeeding studies. Various dietary patterns in the absence of weight gain lead to increased circulating palmitic acid especially when SFAs are the predominant type of fat. Moreover, two studies examining isocaloric diets with increased SFA [74] and decreased fructose [75] support the pathway for ceramide production or reduction, respectively. 1Average American Intake (diets high in SFA, sodium, added sugars, including fructose, and low in fiber) [1], 2Low carbohydrate intake (high fat/SFA diet) [76], 3High carbohydrate intake (refined carbohydrates and added sugars, including fructose) [27, 39]. FAHFA: fatty acid esters of hydroxy fatty acids; CM: chylomicron; VLDL: very low-density lipoproteins.

Palmitic acid from diet induced de-novo lipogenesis

Diets inducing DNL (excess energy, carbohydrate and/or protein intake) more consistently and significantly increase circulating palmitic acid concentrations compared to high-fat (predominantly palmitic acid) diets. King et al. showed that a eucaloric high carbohydrate diet (63% carbohydrate and 17% fat), compared to a moderate fat diet (46% carbohydrates and 34% fat), significantly increased palmitic acid concentrations in red blood cells (2.7 vs. −1.6%), PL (4.1 vs. −2.4%), and cholesterol esters (CE) (11.4 vs. −0.4%) after six weeks in 66 postmenopausal women [26]. In a study of 30 normocholesterolemic men and women, a very low-fat diet (approximately 10% fat and 75% carbohydrates) increased palmitic acid in plasma PL ~7% and CE ~21% compared to a habitual diet (approximately 34% fat and 50% carbohydrates) after two weeks [27]. In several studies with various populations, increases in liver fat have been observed following simple carbohydrate overfeeding and consistently these studies have shown increased production of hepatic palmitic acid [8, 28-30]. A short-term (3-week) overfeeding study (+1,000 kcal/day from simple carbohydrates) including 16 adults (mean BMI: 30.6 kg/m2) demonstrated a 27% increase in liver fat and a strong positive relationship between increases in liver fat and markers of DNL [8]. Moreover, a positive correlation was observed between hepatic DNL and plasma glucose (r=0.53 and p<0.0001) and insulin (r=0.63 and p<0.001) concentrations in individuals with normal BMI, individuals with obesity with normal intrahepatic TG concentrations, and individuals with obesity and non-alcoholic fatty liver disease. Taken together, both hypercaloric and eucaloric high carbohydrate diets significantly increase circulating palmitic acid concentrations via an increase in DNL, but the adverse effects of elevated palmitic acid levels following an eucaloric high-carbohydrate diet are not clear (Figure 1).

Palmitic acid biochemistry, trafficking, and metabolites

Exogenous, meal-derived palmitic acid

Following intestinal absorption, short chain FA (SCFA, <6C), medium chain FA (MCFA, 6-12 C) and long chain FA (LCFA, >12 carbons) are transported in the body differently. The majority of SCFAs are transported via the portal circulation to the liver, however the degree to which MCFAs are delivered to the liver is not fully understood. After being delivered to the liver, SCFAs and MCFAs undergo FA oxidation. LCFAs are not delivered to the liver, but rather are packaged into chylomicrons (CM) and transported through the lymphatic system to the systemic circulation. It has been proposed that stearic acid (C18:0) and palmitic acid may be utilized directly or temporarily stored in TG and PL in the liver for later use [31]. Dietary palmitic acid, while having similar intestinal absorption rates to oleic acid (C18:1n9) and linoleic acid (C18:2n6), is incorporated into the PL membrane at higher rates even when the membrane has a high proportion of palmitic acid [32]. Membrane FA composition affects membrane fluidity and consequently the functional activity of the membrane. An example of this is in hepatocellular carcinoma cells where increasing the palmitic acid concentration reduces membrane fluidity, cellular glucose uptake, lactate production, and consequently reduces ATP generation [13].

Tracer studies of palmitic acid, oleic acid, and linoleic acid show that oleic acid is incorporated more than palmitic acid and palmitic acid more than linoleic acid in CM-TG, plasma non-esterified fatty acid (NEFA), and very low-density lipoprotein (VLDL)-TG; however, palmitic acid and oleic acid are incorporated into plasma CE and PL at a lower rate than linoleic acid. Dietary sources of palmitic acid contain palmitic acid esterified at different locations of the glycerol backbone, which modulates palmitic acid trafficking in the body. Palmitic acid from human breast milk and animal dairy sources often occupies the sn-2 position in TG, which results in preferential incorporation into adipose tissue [33], particularly in subcutaneous fat depots. However, palmitic acid from other animal fat sources may be located at the sn-1 and/or 3 positions, which are less soluble (than the 2 position) and have lower intestinal absorption rates [34]. Lecithin-cholesterol acyltransferase (LCAT) has specificity for the sn-2 position rather than SFA in the sn-1 position of phosphatidylcholine. Fatty acids in the sn-1 position are incorporated into PL and to a much lesser extent into CE [32].

Fatty acids are catabolized to acetyl-CoA via β-oxidation to provide energy for tissues. In rats, differential rates of SFA oxidation correspond with FA chain length, with lauric acid (C12:0) and myristic acid (C14:0) preferential to palmitic acid which is preferential to stearic acid [31]. When comparing SFAs and unsaturated FA, linoleic acid, α-linolenic acid (C18:3n3), and oleic acid are oxidized significantly faster than stearic acid and palmitic acid.

Endogenously derived palmitic acid

A prominent feature of palmitic acid is its endogenous synthesis via DNL. DNL converts excess nutrients, most commonly carbohydrates, to FA in the liver. High-carbohydrate diets can prime and induce hepatic DNL and result in excess accumulation of FA [35, 36]. DNL, in the cytosol, synthesizes long-chain FAs from acetyl-CoA produced from pyruvate following glycolysis in the mitochondria. Mitochondrial acetyl-CoA must be converted to citrate and translocated to the cytosol by the citrate-malate antiporter and then reconverted to acetyl-CoA by citrate lyase. Excessive citrate production promotes FA synthesis and is concurrent with flux through the pentose phosphate pathway. Malonyl-CoA is required for initiation of DNL, so conversion of acetyl-CoA to malonyl-CoA by acetyl-CoA carboxylase, is the rate-limiting regulatory step for DNL. NADPH is produced through the pentose phosphate pathway or cytosolic isocitrate dehydrogenase activity and is required as a reducing agent for FA synthesis [37]. These steps are facilitated by the fatty acid synthase complex and elongate the fatty acyl until palmitoyl-CoA is produced for glycerolipid synthesis in the smooth endoplasmic reticulum. Palmitic acid is the precursor for all other long-chain FA that are synthesized by DNL.

After a meal, net glucose uptake restores hepatic glycogen stores and excess carbohydrate is converted to FA, which are incorporated into TG or oxidized (Figure 2). In the fasted state, net glucose output leads to lipid catabolism in the liver. Hepatocytes express AMP-activated protein kinase, which is a major regulator of lipid synthesis and catabolism in the liver; when AMP-activated protein kinase is activated, fatty acid oxidation is stimulated, and lipogenesis is inhibited [38]. In healthy individuals, insulin activates acetyl-CoA carboxylase by inhibiting AMP-activated protein kinase leading to more malonyl-CoA and an increase in fatty acid synthesis. High PUFA intake suppresses lipogenic enzyme genes like sterol regulatory element-binding protein-1c, which downregulates DNL and stimulates lipoprotein lipase (LpL) to promote FA storage in adipocytes [39]. Other studies have shown that oleic acid suppresses the adverse effects of palmitic acid on endoplasmic reticulum stress, apoptosis, and the insulin signaling pathway by preventing S6K1 activation [40, 41].

Figure 2.

Figure 2.

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Dietary and Endogenous Palmitic Acid Metabolism. Dietary palmitic acid is emulsified and hydrolyzed in the duodenum to become a free fatty acid (FFA) or monoacylglycerol (MAG), which can be absorbed by enterocytes. FFA and MAG are re-esterified into triglycerides (TG) in the cytosol and incorporated into chylomicrons (CM) and transported into a lymph duct for transport to the rest of the body. Lipoprotein lipase (LpL) on extra-hepatic tissues hydrolyze the CM to release FFA from the TG to produce a CM-remnant (CM-R). In the fed state, increased glucose leads to insulin secretion that stimulates GLUT4 and CD36 translocation to the plasma membrane facilitating uptake of glucose and palmitic acid into the adipocyte. Glucose is metabolized to pyruvate, which enters the TCA cycle and produces citrate and subsequently acetyl-CoA. De novo lipogenesis utilizes the acetyl-CoA to synthesize palmitic acid, the primary product of FAS. Palmitic acid can be used as a precursor for FAHFA and ceramide synthesis and have downstream effects as discussed in the paper. 1Average American Intake (diets high in SFA, sodium, added sugar s including fructose and low in fiber [1], 2Low carbohydrate intake (high fat/SFA diet) [76], 3High carbohydrate intake (refined carbohydrates and added sugars including fructose) [27, 39]. DAG: diacylglycerol, MGL: monoacylglycerol lipase, HSL: hormone sensitive lipase, ATGL: adipose triglyceride lipase

Palmitic acid synthesized in the liver by DNL is exported via VLDL, maintaining neutral lipid balance in the liver. In most healthy individuals, FA directly derived from DNL are less than 5% of the total TGs in VLDL; however, the proportion increases up to 40% with higher carbohydrate diets [35, 42] and the proportion is highest with a high carbohydrate diet in the presence of positive energy balance. Low levels of DNL-palmitic acid in VLDL are due to preferential elongation of DNL-palmitic acid to other FA, however, when palmitic acid is dietarily derived it is not modified [43]. A common misinterpretation is that only 5% of total TGs are DNL-derived, however this fails to account for recirculation of FA between the adipose and liver. In fact, there is no upper limit to the quantity of circulating FA originally derived from DNL.

Fatty acid synthase activity and consequent DNL are increased in obesity [42]. Extensive evidence supports increased hepatic DNL in response to increased circulating glucose and insulin [44, 45]. In insulin-resistant obesity, reduced expression of GLUT4 impairs adipocyte DNL and alters the lipid content secreted by adipose tissue [45]. In humans, DNL in the liver and adipose tissue are quantitatively comparable in the absence of stimulation. After oral glucose ingestion, the expression of lipogenic genes in adipose tissue is only minimally stimulated, but highly expressed in the liver [46]. Feeding studies have evaluated the impact of overfeeding and the effect of hypercaloric versus eucaloric diets on liver fat accumulation. Saturated fat and fructose (from added sugars) increase intrahepatic triglycerides (IHTG) resulting in insulin resistance and ceramides production [47]. The major hepatic lipid influx is from adipose tissue lipolysis (specifically NEFAs), as well as hepatic DNL primarily from palmitic acid derived from glucose, fructose, or both [47]. The ensuing insulin resistant state increases lipolysis resulting in increased flux of fatty acids from adipocytes to the liver as a consequence of insufficient insulin-mediated suppression of hormone sensitive lipase. [47].

Palmitic acid in triglyceride-rich lipoproteins (chylomicrons and VLDL)

CM production coincides with rapid appearance of meal-derived triglycerides, glucose and amino acids. FA hydrolyzed from lipoprotein TG but not taken up by extra-hepatic tissues, constitute “spillover,” and enter the circulation as free FA. Spillover contributes ~20% to the total circulating NEFA, and a lower proportion in individuals with higher BMI [48]. The relative content of apoB differs with the relative FA content of CM. CM-TG with relatively higher palmitic acid to linoleic acid content are smaller and have a significantly greater apoB/TG ratio [49]. Oleic and linoleic acid increase CM number or size, respectively, to a greater extent than palmitic acid; oleic-acid-rich TG activates microsomal transfer protein to a greater extent than linoleic or palmitic acids [50].

The FA in VLDL are derived from both extant FA and de novo FA. Excess hepatic FA or CM remnants are extant FA sources of VLDL-TG synthesis while carbohydrate-mediated hepatic DNL predominantly produces palmitic acid de novo [51]. VLDL produced during DNL in response to a low-fat diet have significantly higher palmitic acid content than from high-fat diet [52]. Exogenous palmitic acid begins to appear in VLDL-TG within 3 hours of dietary intake [53]. The composition of VLDL shifts during the 24 hours following a palmitic acid-rich meal: within the first 7 hours, VLDL-linoleic acid content increases, however by 24 h linoleic acid decreases to pre-meal levels but thereafter oleic acid and palmitic acid are the most abundant VLDL-FA [32]. In concert with DNL regulation, VLDL secretion from the liver curbs palmitic acid accumulation and/or an imbalance in SFA/UFA in cell membrane PL [2].

Palmitic acid in non-esterified fatty acids

Following a meal, total NEFA availability is decreased by >70% in healthy individuals [54], a process mediated by insulin-dependent suppression of hormone sensitive lipase activity in adipocytes to sequester, or remove, NEFA from circulation. This process limits NEFA availability to tissues following a meal and facilitates glucose utilization. In individuals without metabolic syndrome, an exogenous glucose challenge leads to an 85% suppression of circulating palmitic acid (~ 20% of total NEFA), which is greater suppression than the average NEFA suppression (75%) [54], meaning that adipocytes respond to the glucose challenge with great restriction of circulating palmitic acid compared to other FA. Patients with impaired glucose tolerance, due to metabolic syndrome, obesity, and insulin resistance, have less suppression of circulating plasma NEFA and palmitic acid due to less adipose tissue sequestration [54, 55], corresponding to higher levels of circulating palmitic acid. Fatty acid spillover, the inability of adipocytes and other cells to accommodate sufficient fatty acid uptake from CM and VLDL, also contributes to higher circulating NEFA, particularly palmitic acid, since palmitic acid is one of the more abundant FA in CM and VLDL [32].

Fates of circulating palmitic acid

Endogenous and exogenous TG in CM and VLDL compete for a common catabolic pathway mediated by LpL in extrahepatic tissues [56, 57]. CM are cleared from the circulation very quickly with a half-life of less than 1 hour, while the half-life of VLDL is ~4-6 hours [57]. With respect to dietary palmitic acid, it is packaged into CM that are transported to adipocytes following a meal, whereas DNL and recirculation of extant palmitic acid are responsible for palmitic acid appearance in VLDL particles, which are prevalent between meals. Hence, CM and VLDL deliver palmitic acid to tissues for β-oxidation or storage. For this reason, expression of LpL regulates the fate of CM and VLDL palmitic acid. Post-prandial LpL expression is insulin sensitive and high in adipocytes [58], but low during fasting, facilitating a switch in the destination of circulating palmitic acid towards tissues utilizing it for energy. Insulin induces LpL expression in adipose tissue, however in skeletal muscle LpL expression is induced by exercise [59]. LpL-derived and albumin-bound FA, including palmitic acid, can also be taken up by cardiac and skeletal myocytes where they can be utilized as an energy source.

Palmitic acid as a precursor for sphingolipids/ceramides

Ceramides function to coordinate cell growth, differentiation, senescence, and death, as well as act as a signaling molecule in insulin resistance, inflammation, and neurodegenerative diseases. Metabolic control is ceramide specific. Production of ceramides and other bioactive sphingolipids is influenced by dietary FA. Synthesis of ceramides is increased with high intake of SFAs and decreased when eicosapentaenoic, docosahexaenoic (C22:6n3), and oleic acid are abundant [40, 60]. In de novo synthesis, palmitoyl CoA is a precursor for ceramide synthesis, which occurs in the endoplasmic reticulum by the condensation of palmitic acid and serine, the rate-limiting step [61]. Ceramide synthase has six isoforms that correspond to different chain length ceramides that have different functions in the body; for example, palmitic acid exposure leads to C16:0 ceramides [62]. Ceramides can also be synthesized in the plasma membrane by activation of sphingomyelinase, which hydrolyzes sphingomyelins to ceramides [61]; this process is up-regulated by palmitic acid exposure, which increases the expression and activity of neutral sphingomyelinase [63]. Finally, ceramides can be synthesized through a sphingolipid recycling pathway, which breaks down complex sphingolipids into sphingosine to be re-acylated into ceramide [61]. In hepatocytes, increased palmitic acid causes endoplasmic reticulum stress and the release of extracellular vesicles that contain ceramides [63]. Alternatively, exposure to oleic acid, even alongside exposure to palmitic acid, increases the expression and activity of carnitine palmitoyltransferase 1, which transports FA into the mitochondria for β-oxidation, and results in lower ceramide concentration in the cell [40]. An eight-week overfeeding intervention with palmitic- and linoleic acid-enriched diets demonstrated opposite effects on ceramide synthesis in individuals with obesity; serum ceramides were significantly higher with palmitic acid than with linoleic acid and the same trend was present with adipose tissue ceramides [7]. Following synthesis, ceramides act to regulate stress, lipotoxicity, and inflammation as a second messenger [60]. Longitudinal studies suggest higher levels of ceramides are associated with increased risk for developing insulin resistance and T2DM. Moreover, ceramides increase early in disease progression and there is robust evidence that they are a biomarker of risk for insulin resistance, T2DM and CVD [64]. While there is evidence of an association between 16:0 ceramides and increased risk for these outcomes, there are no intervention studies that have shown that reduction of 16:0 ceramides lowers the risk for them. The biological plausibility of the potential causal relationship should be examined in animal models and randomized control trials with humans.

Palmitic acid as a precursor for branched fatty acid esters of hydroxy fatty acids

DNL is important for the synthesis of lipokines such as palmitoleic acid and FAHFAs [39]. FAHFAs are present in animal and plant foods; however, most functional effects are attributed to endogenously synthesized FAHFAs [22]. Discovered in 2014, FAHFAs have been shown to have potential anti-inflammatory and anti-diabetic effects. One of the predominant FAHFAs is palmitic-acid-hydroxy-stearic-acid, which is formed by palmitic acid esterified to hydroxylated stearic acid. Palmitic-acid-hydroxy-stearic-acid has been shown to stimulate insulin secretion in human pancreatic beta cells in vitro and increase insulin-stimulated glucose uptake in murine adipocytes in vitro [22]. In another study conducted with a small number of participants, FAHFAs were decreased in patients with severe obesity (n=18) and increased in response to a high SFA overfeeding for one week, whereas there were no differences in total FAHFAs in participants with (n=10) and without (n=10) T2DM [65].

Agonists for G-protein coupled receptors

Recent research has focused on PUFAs as signaling molecules with the identification of free fatty acid receptors 1-4 (FFAR1-4), a series of G-protein coupled receptors having FA as endogenous ligands [66]. Of these, long chain FA with ≥10 carbons are endogenous ligands for FFAR1 and FFAR4, implicating palmitic acid as a ligand. The broad biology of FFAR1 [67] and FFAR4 [66] are reviewed elsewhere. The potency, or concentration required to activate the receptor, is nearly the same for all dietary FA: palmitic acid was 5.9 μM for FFAR1 and 5.3 μM for FFAR4, which is in the range for all other FA measured (4.5 to 5.9 μM). In contrast, the efficacy, which is the maximal activation, is low for palmitic acid. Palmitic acid achieved 55% of the activation compared with lauric acid at its maximal stimulation of FFAR1 and only 33% of lauric acid at its maximal activation of FFAR4 [68]. Thus, palmitic acid functions as a partial agonist and in matrices containing better activators, such as monounsaturated fatty acids or PUFA, palmitate may act to inhibit FFAR1 and FFAR4 in vivo.

Other palmitic acid effects that promote atherogenesis

Beyond our well-established understanding of the LDL-C raising effects of palmitic acid, and what has been discussed above, there are other emerging biological mechanisms for how palmitic acid may increase CVD risk. Research has shown that habitual consumption of a diet high in SFA (and consequently palmitic acid) has a detrimental effect on endothelial function [69] as does a single high SFA meal [70] In a recent review, Yamagata [71] concludes that palmitic acid increases expression of intracellular adhesion molecules (ICAM-1, IL-6, IL-8 and TLR-2), and endothelial cell vascular cell adhesion molecule (VCAM-1), all of which enhance monocyte migration [72] There is other evidence that palmitic acid increases the production of reactive oxygen species (ROS) activating apoptosis-related proteins in cultured endothelial cells [73]. Additional research reviewed by Yamagata has demonstrated multiple effects of palmitic acid on the macrophages that promote atherosclerosis, including increased cyclooxygenase activity and induction of IL-1ß, both of which increase inflammation, activation of NLRP3 leading to the production of ROS, and an increased expression of lectin-like oxidized LDL receptors leading to formation of foam cells. Collectively, these findings suggest that palmitic acid adversely affects the function of vascular endothelial cells and macrophages, which would be expected to promote atherogenesis.

Conclusions and Future Directions

Circulating palmitic acid is derived from exogenous sources and synthesized endogenously, both of which are modulated by dietary intake. Observational evidence suggests a positive association between palmitic acid intake, circulating palmitic acid and CVD risk. However, conditions that increase circulating palmitic acid levels have not been extensively investigated. The contribution of palmitic acid consumed as part of a eucaloric diet to circulating palmitic acid levels remains unclear. Results from several studies suggest that under hypercaloric conditions with overfeeding of fat (as palmitic acid) there is an increase in circulating palmitic acid. Similarly, overfeeding carbohydrates increases circulating palmitic acid, likely as a result of increased DNL. Concomitantly, these hypercaloric conditions increase insulin resistance, circulating ceramide concentrations and liver fat. Collectively, the evidence reviewed suggests that palmitic acid (from exogenous and endogenous sources) may increase CVD risk. Additionally, in the context of sustained intake of a hypercaloric diet leading to overweight/obesity, ensuing insulin resistance, and increased hepatic fat deposition, DNL is upregulated leading to increased circulating palmitic acid levels, which would be associated with possible adverse CVD outcomes. In this metabolic milieu it is not possible to clarify the relative contribution of increased circulating palmitic acid, versus insulin resistance and increased hepatic fat, to the heightened risk of adverse CVD outcomes.

To advance the field, the following areas of research should be prioritized: 1) characterization of the contribution of palmitic acid intake to circulating palmitic acid levels under eucaloric and hypercaloric conditions in healthy individuals as well as those that have metabolic impairments; 2) elucidation of the influence of circulating palmitic acid concentrations on circulating concentrations of ceramides and FAHFAs; 3) identification of molecular mechanisms implicated in the pathogenesis of cardiometabolic disease that are influenced by circulating palmitic acid concentrations; and 4) how palmitic acid affects macrophage biology, cellular recruitment, endothelial function and atherogenesis. This research will increase knowledge about dietary modulation of circulating palmitic acid levels, which may inform dietary guidance and therapeutic interventions. In addition, establishing the role palmitic acid plays in endogenous synthesis of ceramides and FAHFAs will contribute to understanding metabolic regulation of palmitic acid. Finally, given the challenges of studying diet-disease relationships (which typically require studies of long duration that are adequately powered that typically require a large sample size), causal inference is strengthened by identification of biologically plausible mechanisms to explain epidemiological findings and evidence from clinical trials.

In conclusion, we have an in-depth understanding of the LDL-C-raising effects of palmitic acid, which is the basis of our current dietary recommendations for decreasing SFA to reduce CVD risk. Emerging evidence has provided new insight about other mechanisms by which palmitic acid may contribute to CVD risk. A better understanding of these new mechanisms will inform future dietary recommendations including guidance for healthy dietary patterns that promote CVD health. Although more research is needed to understand the effects of high saturated fat diets and low-fat diets on palmitic acid metabolism and CVD risk, we also need a better understanding of what the effects of currently recommended dietary patterns are on palmitic acid metabolism. This information will provide a stronger evidence base to support future dietary recommendations.

Highlights.

  • Plasma palmitic acid is derived from dietary fat and also from de novo lipogenesis (DNL) and lipolysis

  • A low-fat diet promotes palmitic acid synthesis and a high-fat diet provides palmitic acid from food

  • Palmitic acid increases CVD risk by raising LDL-C, synthesis of ceramides and branched fatty acid esters of hydroxy fatty acids (FAHFAs) derived from palmitic acid

Funding Sources and Disclosures:

NIH 1R01HL152215-01 (Gregory C Shearer)

NIH T32GM108563 (Carmen E. Annevelink)

Footnotes

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Conflict of Interest

The authors have no conflicts of interest to report.

Declaration of Generative AI in Scientific Writing

Generative AI was not used in the writing of this review.

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