Introduction
Palmitic acid (PA) is a 16-carbon long-chain saturated fatty acid (SFA),1,2 which is widely found in animals and plants.3 It is an essential constituent acid of adipose tissue and the most abundant SFAs in the body,4 accounting for approximately 44–52% of the body’s total fat content5 and 28–32% of the total serum fatty acid (FA).6
Cardiovascular diseases (CVD) is one of the deadliest diseases worldwide.7 CVD mainly includes coronary heart disease, cerebrovascular disease, peripheral artery disease, rheumatic heart disease, congenital heart disease, deep vein thrombosis, and pulmonary embolism.8 In addition, atrial fibrillation is very closely linked to atherosclerosis (AS) and has largely the same pathophysiological basis as other CVD: endothelial dysfunction and inflammation, coronary artery disease is an important and clinically relevant risk factor of atrial fibrillation.9 According to the World Health Organization, 17.3 million people died from CVD in 2016, accounting for 31.5% of all deaths. This number is expected to increase to 23.6 million by 2030.8 The mortality rate of CVD has exceeded that of cancer, infectious diseases, maternal diseases, and neonatal diseases.10 Hyperlipidaemia (elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDL-C)), Systemic inflammation, and oxidative stress play a crucial role in the development of CVD.11–14
Emerging evidence indicates that elevated circulating FA levels correlate with CVD incidence, and free fatty acids show diagnostic potential as early biomarkers for AS.15–20 In vivo and in vitro experiments evidence suggests potential mechanisms linking PA intake with CVD pathogenesis.21,22 Epidemiological studies also indicate that high dietary PA exposure associates with increased CVD risk across diverse populations.23,24 Elevated serum PA concentrations have been proposed to heighten atrial fibrillation risk primarily through PA’s impact on endothelial dysfunction and inflammation.25 However, critical gaps persist in current research: the analysis of PA’s biosynthetic pathways remains incomplete, with insufficient mechanistic delineation specific to individual pathologies, particularly AS, ischemic heart disease (IHD), and ischemic stroke (IS); in addition, lack of translational research frameworks connecting PA-related molecular mechanisms to therapeutic strategies; finally, while substantial evidence supports PA’s detrimental cardiovascular effects, several studies report context-dependent outcomes (Table 1). To address these gaps, this review: Systematically synthesizes PA’s anabolic pathways and pathological mechanisms in AS, IHD, and IS; Identifies novel targetable nodes for CVD prevention/treatment by pinpointing therapeutically exploitable sites within key biological pathways.
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Table 1 Palmitic Acid Associations with Traditional Cardiovascular Risk Factors
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Methods
A systematic search was performed across four electronic databases (PubMed, Scopus, Web of Science, and Google Scholar) to comprehensively identify literature examining the association between palmitic acid and specific cardiovascular diseases, namely atherosclerosis, ischemic heart disease, and ischemic stroke. Search results were merged and deduplicated. Initial study inclusion/exclusion was determined by screening titles and abstracts. The review encompassed literature published through December 2024.
The Anabolic Pathways of Palmitic Acid
Endogenous Synthesis and Exogenous Uptake of Palmitic Acid
Palmitic acid is mainly synthesized in the liver. In the de novo synthesis, glucose and glutamine produce pyruvate by glycolysis, which undergoes the tricarboxylic acid cycle in the mitochondria to produce citrate. And then the citrate is cleaved in the cytoplasm by ATP-citrate lyase (ACLY) to Acetyl-CoA and oxaloacetate. Acetyl-CoA is then carboxylated to malonyl-CoA by acetyl-CoA carboxylase (ACC) and condensed by fatty acid synthase (FASN) in a repeated reactions to generate PA.30,31 The endogenous synthesis of PA is controlled precisely under normal circumstances. However, when carbohydrate intake is excessive, the carbohydrate response element-binding protein (ChREBP) is activated, upregulation of the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) and resulting in insulin production, which subsequently increases PA production32–34 (Figure 1).
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Figure 1 Endogenous synthesis and exogenous uptake of palmitic acid. In the de novo synthesis, glucose and glutamine are enzymatically catalyzed to produce citrate, which is cleaved to acetyl-CoA and oxaloacetate. Acetyl-CoA is carboxylated to malonyl-CoA, which is condensed by the repeated actions of FASN to produce PA. In the process of exogenous uptake, dietary fat is digested into free fatty acids and monoglycerides through the emulsification of bile acids in the duodenum and upper jejunum, which are then absorbed and converted into TG by intestinal epithelial cells, and then combined with apolipoproteins to form chylous particles, which enter the lymphatic system and the ultimately the bloodstream.
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Exogenous Uptake Pathway of Palmitic Acid
Palmitic acid is found in plant oils including palm oil, peanut oil, and coconut oil, as well as in animal fats like butter and cream. Therefore, the human body can also obtain PA through exogenous dietary intake.35,36 The primary sites for digestion and absorption of fats in the human body are the duodenum and the upper jejunum. When the body consumes fats containing PA from the diet, they are emulsified by bile acids to form hydrophobic fat globules, which are then further broken down into smaller droplets. These droplets are subsequently hydrolyzed by pancreatic lipase into free fatty acids and monoacylglycerol, which are absorbed by the intestinal epithelial cells. In the endoplasmic reticulum (ER) of the epithelial cells, free fatty acids are converted into TG, which then combine with apolipoproteins. These TG, together with apolipoproteins, are transported through chylomicrons to the lymphatic system and eventually enter the bloodstream37,38 (Figure 1).
Metabolism of Palmitic Acid
The distribution and metabolism of PA in tissues is strictly controlled by the organism, which normally regulates the de novo synthesis pathway according to the amount of exogenous PA consumed.39,40 First, PA as a kind of FA, have the capability of providing the body with energy through the process of oxidative catabolism.41,42 PA combines with carnitine to produce an acylcarnitine molecular, and then the acylcarnitine molecular is transported across the mitochondrial membrane to the mitochondrial matrix to generate a molecule of nicotinamide adenine dinucleotide (NADH), a molecule of flavin adenine dinucleotide, reduced (FADH2), and an acetyl-CoA, which is eventually consumed as energy for the body.43 Secondly, PA is elongated or desaturated for conversion to other FA or compounds,44 which are produced in the presence of FA elongases (elongation of very long-chain fatty acids 1–7 (ELOVL1-7)) to produce longer chain FA (eg, stearic acid (SA) and arachidonic acid).45 Moreover, PA synthesized endogenously in adipocytes is converted to other FA or compounds through elongation and desaturation in preference to exogenous PA, thus ensuring that the concentration of PA in tissues is within the normal range to maintain cell membrane fluidity and insulin sensitivity.46,47 Finally, PA itself can be transformed into an important component of biofilms (phospholipids), which plays an important role in biological processes (eg, cellular proliferation, reproductive processes, and intracellular transport). PA was found to generate phosphatidylcholine and phosphatidylethanolamine (PE) by deacylation in rat hepatocyte, the final synthesis of membrane phospholipids.48 This process is regulated by membrane-binding transcription factors and can further regulate lipid synthesis.49
In obese subjects, the activity of stearoyl coenzyme a desaturase 1 (SCD1) was increased, and SCD1 was associated with insulin sensitivity.46 However, under pathological conditions including insulin resistance and chronic nutritional imbalance, this regulatory mechanism can be disrupted, leading to excessive PA deposition in the liver and eventually to a series of CVD.50,51 Several studies have measured plasma PA concentrations in healthy subjects, indicating a range of 100~409 µM. Nevertheless, patients with diabetes, hypertriglyceridemia, and CVD have elevated plasma PA levels (Table 2).
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Table 2 Plasma Palmitic Acid Levels
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Palmitic Acid and Cardiovascular Diseases
Palmitic Acid and Atherosclerosis
Atherosclerosis is the basis of most CVD and causes of death, for example, coronary heart disease and stroke.58 It is characterized by the endothelial dysfunction and inflammation, form cells formation from macrophage, atherosclerotic plaque formation in the intima of arteries and apoptosis,59–61 which may result in acute cardiovascular events due to plaque rupture and thrombosis.62 Studies have demonstrated that the high concentrations of PA in blood are involved in the formation of AS through a variety of biological processes, including hyperlipidaemia,63,64 inflammation,65 vascular endothelial damage,66 form cells formation,67 and downregulation of apolipoprotein M (APOM).68
Palmitic Acid Induces Hyperlipidemia
There is an increased risk of CVD associated with high levels of TC, LDL-C, and lower levels of HDL-C.69,70 PA can induce AS by altering blood cholesterol levels, particularly through elevating LDL-C levels.63,64 PA inhibits the expression of low density lipoprotein (LDL) receptors and accelerates the secretion of very low-density lipoprotein (VLDL) from the liver.51 Genes related to lipid transport, adipogenesis, lipid droplet formation, and glucose and FA metabolism were found to be upregulated after incubation with PA in human hepatocytes cultured in vitro, similar effects were observed in primary cultures of human pancreatic islets.71,72 Specifically, PA promoted lipid accumulation by upregulating the CCN1/integrin α5β1 pathway.73 Lipid accumulation and apoptosis were also observed in PA-treated human kidney-2 (HK2).74 Increased dietary levels of 18:2(n-6) FA lead to lower total and LDL-C levels, while at low dietary levels of 18:2(n-6) FA, increased PA content leads to a significant increase in total and LDL-C levels.75 Meanwhile, in a controlled metabolic feeding study, PA intake promotes elevated blood cholesterol levels, consistent with previous studies.76–78 In addition, PA also induces insulin resistance, leading to impaired lipid metabolism. Prolonged exposure of cultured human, rat or mouse islets to PA leads to reduced insulin transcription, impairment of glucose-induced insulin secretion, and finally to β-cell apoptosis.79–81 PA promotes β-cell apoptosis via mTOR-mediated downregulation of protein kinase B (AKT).82 In human umbilical cord endothelial cells, PA induces insulin resistance by upregulating human regulator of G protein signaling 2 (RGS2) expression, which inhibit insulin-mediated AKT phosphorylation83,84 (Figure 2).
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Figure 2 Overview of the mechanisms by which palmitic acid promotes atherosclerosis. PA promotes the progression of by inducing hyperlipidemia, vascular endothelial cell injury, foam cell formation, downregulation of APOM, and proinflammatory effects. Its proinflammatory effect is by activating TLR2 and TLR4, enhanced LPS production and synergistic interactions with LPS, promoting FABP4 expression, amplification of proinflammatory T-cell responses, and induction of ER stress and oxidative stress (↑: increase/activation; ↓: decrease/inhibition).
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Palmitic Acid Mediates Inflammation
Palmitic Acid Promotes the Production of Inflammatory Factors
PA has been shown to directly increase levels of interleukin-6 (IL-6) in vivo and in vitro.85–87 PA upregulates the expression of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) in vascular smooth muscle cells (VSMCs), thereby triggering an inflammatory response in cardiac fibroblasts and inducing apoptosis in VSMCs.88 PA increases the level of the cysteine-rich angiogenic inducer 61 (CYR61) in endothelial cells, thereby stimulating the production of pro-inflammatory cytokines and pro-apoptotic factors.89 PA also induces the secretion of interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and TNF-α by peritoneal macrophages, which activated the inflammatory process in LDLr KO mice and ultimately induced AS formation.90 In microvascular endothelial cells (EOMA lineage), palmitate stimulates the activation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome.88 Further studies showed that PA treatment of mouse primary macrophages induced the formation of crystals within the macrophages, which activated the NLRP3 inflammasome, resulting in lysosomal dysfunction and increased IL-1β release91 (Figure 2).
Palmitic Acid Activates Toll-Like Receptor 4 (TLR4) to Promote Inflammation
During the inflammatory response, toll-like receptors (TLR) serve as receptors for lipopolysaccharide (LPS).92–94 Several studies have demonstrated that PA is a TLR agonist that activates TLR4 and TLR2, and induces dimerization among TLR2 and TLR1, TLR2 and TLR6, or TLR4 and TLR6.95,96 TLR4 translocates into lipid rafts after activation and recruits its downstream adapter molecules (MyD88 and TRIF) to the rafts. After dimerizing with MyD88 or TRIF, initiates pro-inflammatory cytokine and type I interferon production.84 In addition, activated TLR4 forms a complex with myeloid differentiation protein 2 (MD2), which triggers downstream signaling. However, it is uncertain whether PA is a direct agonist of TLR4-MD2.97 During the activation of TLR4, atypical protein kinase Czeta (PKCζ) is triggered by RhoA, next PKCζ activates transforming growth factor β-activated kinase 1 (TAK1), which then participates in the activation of NF-κB,98 which results in the production of inflammatory cytokines (eg, TNF-α and IL-6).90 PA promoted the TLR4/phosphorylated-NF-κB signaling pathway by inhibiting Krüppel-like factor 4 (KLF4), upregulated Galectin-3 expression, and improved insulin resistance in macrophage99 (Figure 2).
Palmitic Acid Activates the Proinflammatory Function of T Cells
T cells are an instrumental component of adaptive immunity and account for 10% of all cells in atherosclerotic plaques.100,101 Using single-cell sequencing techniques, T cells were found to account for approximately 30–65% of white blood cells in atherosclerotic plaques in humans and mice.102–104 CD4+ T cells are the predominant T cell subtype in AS and exacerbate atherogenesis in immunodeficient Apoe-/- mice.105 Researchers found that both CD4+ T cells and CD8+ T cells were increased at atherosclerotic lesion sites associated with acute coronary syndrome.106 PA activates the proinflammatory function of T cells in four ways: metabolism, activation, proliferation, and polarization.107 There is evidence that PA increases insulin receptors (IR), insulin-like growth factors 1 (IGF-1), glucose transporter type 4 (GLUT4), and insulin receptor substrate 1 (IRS1) on the surface of T cells, resulting in T cell activation. PA also stimulates the proliferation of T cells and induces the polarization of T cells into proinflammatory subpopulations (Th1 cells and Th17 cells), which then induce an inflammatory response.107 The addition of 1 mM PA to peripheral blood mononuclear cells activated with anti-CD3 and anti-CD28 increased the proportion of Th1 and Th17 cells, while decreasing that of TH 2 and Treg cells. After in vitro exposure to PA, CD4+ T cells or CD8+ T cells isolated from five healthy, non-diabetic, and glucose-tolerant individuals were found to be activated in a time and concentration-dependent manner108 (Figure 2).
Palmitic Acid Promotes Inflammation in Synergy with LPS
A high-fat diet increases the levels of short-chain FA by altering the gut microbiome, which leads to elevated levels of LPS and enhanced activation of TLR4.109 PA also increases ceramide production through de initio synthesis and sphingolipid hydrolysis, thereby enhancing IL-6 expression and TNF-α stimulation induced by LPS.110 Researchers fed mice both LPS and a high-fat diet rich in PA, which accelerated thoracic aortic atherosclerosis.111 In human aortic endothelial cells (HAECs) and cardiac microvascular endothelial cells (MICECs), co-treatment with LPS and PA increased IL-6 expression at 36 hours111 (Figure 2).
Palmitic Acid Promotes the Expression of Fatty Acid‑binding Protein 4 (FABP4)
As a cytoplasmic FA carrier protein, FABP4 regulates lipid transport and responses in cells, and is associated with metabolic and inflammatory pathways.112–115 FABP4 bind a long-chain FA, including PA, SA, oleic acid (OA), linoleic acid (LA), and facilitates the translocation of FAs to specific organelles in the cell (eg mitochondria, peroxisomes, ER, and nucleus), regulates enzymatic activity, and stores excess FAs as lipid droplets.116 The FABP4 protein has a high affinity for free monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) in cells under normal conditions, however, under oxidative stress conditions, the conformation of FABP4 changes, losing its affinity for most FA (except PA), and triggers an inflammatory response.116 PA increases FABP4 protein expression in macrophages via ER stress.117,118 The genetic ablation of FABP4 in macrophages showed inhibition of inflammatory signaling, reduced NF-κB pathway activation, and reduced ER stress, protecting mice from AS and dyslipidemia.119,120 In C2C12 skeletal muscle cells, overexpression of FABP4 protein decreases expression the expression of Sirtuin 3, uncoupling protein 2 (UCP2), and Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), ultimately leading to increased ROS production in mitochondria and inflammation121–123 (Figure 2).
Palmitic Acid Activates ER Stress
The ER is involved in the biosynthesis of cholesterol, steroids, and other lipids. A high concentration of free fatty acids (eg PA) may disrupt lipid metabolism, which triggers stress in the ER. When PA is transformed into phospholipids and diacylglycerol (DAG), it accumulates in the ER, causing disruptions in the structure of the ER and activation of the stress sensors.124–126 The extracellular signal-regulated kinase (ERK) pathway mediates translation of CCAAT/enhancer binding protein (C/EBP) homologous proteins and genes involved in autophagy that are dependent on activating transcription factor 4 (ATF4). Inositol-requiring enzyme 1α (IRE1-α) mediates the expression of tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulated kinase 1 (ASK1)/C-jun N-terminal kinase (JNK). They contribute to the ability of stress cells to maintain autophagy, which ultimately triggers ER oxidative and inflammatory signaling pathways leading to apoptosis.127–131 Phosphorylated ERK, IRE1α, and JNK activation are elevated in both adipose tissue and liver of high fat diet fed mice, which triggers ER stress, eventually leads to apoptosis.132–135 By upregulating ATF4 and C/EBP homologous protein (CHOP) expression, decreasing cytoplasmic NAD+/NADH, and reducing Sirt1 activity, PA induced ER stress in H9c2 myogblasts.136 Heart-specific sirt1 knockout mice fed a high palmitate diet were found to express higher levels of CHOP and ATF4.136 In obese individuals and type 2 diabetes mellitus (T2DM) patients, chronic exposure of β-cells to FA results in ER stress and lipotoxicity137 (Figure 2).
Palmitic Acid Induces Oxidative Stress
Increased reactive oxygen species (ROS) are the primary cause of palmitate-induced oxidative stress. PA enhances ROS production by promoting lipid uptake in podocytes, and the activity calcium/protein kinase Cα/NADH oxidase 4 (NOX4) pathway in endothelial cells, inhibited mitochondrial respiratory chain complex I and complex III. And the activity of adenine nucleotide carrier protein (ADP/ATP carrier protein).138–141 Normal mouse hepatocytes AML12 treated with PA. Lipid accumulation, expression of total ROS, mitochondrial ROS, NOX4, inflammasomes, and IL-1β were detected in hepatocytes after 24 h142 (Figure 2).
Palmitic Acid Induces Vascular Endothelial Injury
Vascular endothelial injury is an important pathological process in the process of AS. Endothelial dysfunction, characterized by impaired vasodilation, inflammation, and thrombosis, triggers future CVD.143 Reduced endothelial progenitor cells are independent predictors of CVD morbidity and mortality.144 Lipotoxicity of PA decreases immune surveillance protein DDX58/Rig-1 expression and activity, leading to impaired autophagy and apoptosis;145 apoptosis in vascular endothelial cells induces endothelial injury and promotes AS progression.146,147 A member of the angiopoietin-like protein family involved in lipid metabolism promotes endothelial cell proliferation and inhibits PA-induced endothelial cell injury by increasing autophagy, which may inhibit AS.66 Also, activation of the interferon regulator 3 (IRF3) pathway causes endothelial inflammation.148 Nitric oxide (NO) from enzymatic NO synthases (NOS) system importantly contributes to vascular homeostasis, in addition to the classical NOS system, NO can also be generated via the nitrate-nitrite-NO pathway.149 The addition of PA to HAECs resulted in decreased cell viability, reduced intracellular NO production, increased migratory capacity of HAECs, and cellular oxidative stress, ultimately leading to endothelial-to-mesenchymal transition.150 In endothelial cells, PA upregulated the expression of phosphorylated p38, JNK, and caspase-3, thereby increasing endothelial apoptosis dose- and time-dependently.151,152 Patients with coronary artery disease showed significantly higher levels of phosphorylation of p38 and mitogen-activated protein kinase (MAPK) in endothelial progenitor cells than healthy individuals.153 Inhibition or knockout of p38 and MAPK significantly increases the number of circulating endothelial progenitor cells154 (Figure 2).
Palmitic Acid Promotes Foam Cells Formation
Form cells is one of the major causes of AS, which is due to the accumulation of oxidized LDL (oxLDL) in the arterial intima. Macrophages absorb accumulated oxLDL and form cells. The presence of high levels of PA in the blood enhances the ability of macrophages to take up oxLDL and produce more form cells. OxLDL is a dysfunctional lipid metabolite that is a major promoter of the prothrombotic state in both animal models and human patients.67,155 In macrophages, PA enhances lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression, promotes oxLDL uptake, a process mediated mainly through the ROS-p38 MAPK pathway.156 5-hydroxytryptamine (5-HT) takes part in platelet aggregation, vasoconstriction, proliferation of VSMCs, ER function, and macrophage foam cell formation, play a key role in the development of AS.157,158 In vitro experiments, exposure of macrophages and human umbilical vein endothelial Cells (HUVECs) to oxLDL or PA demonstrated that activation of 5-HT2A receptor regulates TG synthesis and oxLDL uptake by activating PKCε, resulting in the formation of lipid droplets and even foam cells.159 PA increases CD146 expression in macrophages, promoting foam cell formation and disrupting migration-related signaling,160 by activating JNK signaling and inhibiting STAT3 activation, CD146 (Gp130) promotes proinflammatory polarization of M1-like adipose tissue macrophages (ATMs)161 (Figure 2).
Palmitic Acid Induces Apolipoprotein M Downregulation
Palmitic acid can downregulate the expression of human APOM, promote the accumulation of cholesterol in the blood and induce the development of AS. APOM facilitates HDL metabolism and stabilization, which can reduce blood cholesterol levels, with anti-AS, anti-inflammatory and antioxidant effects.162 Generally, it is found in hepatocytes and renal tubular epithelial cells, and is weakly expressed in colorectal tissues.163,164 APOM has been shown to be a possible HDL-carrying receptor for sphingosine 1-phosphate, which enhances HDL-mediated antioxidant effects.165,166 APOM plays a role in the formation of preb-HDL,167,168 PA significantly inhibited APOM gene expression in HepG2 cells, and the peroxisome proliferator-activated receptor β/δ (PPAR β/δ) antagonist GSK3787 completely reversed PA-induced downregulation of APOM expression, indicating that PA-induced downregulation of APOM expression is mediated through the PPAR β/δ pathway.68 A key regulator of lipid metabolism, peroxisome proliferator-activated receptor (PPAR), is expressed in platelets. This receptor upregulates the transcription of lipid metabolizing enzymes, including carnitine palmitoyl coenzyme A transferase-I (GPT-I) and acyl-CoA oxidase, both of which are important to thrombosis and hemostasis169,170 (Figure 2).
Palmitic Acid and Ischemic Heart Disease
Ischemic heart disease is heart disease caused by narrowing/occlusion of the coronary arteries or by ischemia, hypoxia, or necrosis of the heart muscle due to spasm of the coronary arteries. Approximately 40–80% of the heart’s energy comes from FA, several cohort studies have revealed, compared with healthy young subjects, patients with chronic heart failure, myocardial ischemia, T2DM, and obese individuals elevated levels of free fatty acids (include PA) in the blood.171–177 Additionally, there are studies that indicate that PA levels in adipose tissue are related to IHD incidence. Insull et al found that SA (18:0), lauric acid (12:0), palmitoleic acid (16:1), myristic acid (14:0), and LA (18:2) acids were associated with coronary artery disease, and PA (16:0) content in adipose tissue was associated with plasma cholesterol levels.178 A study by Lee et al compared the FA composition of adipose tissue in two races with different prevalences of coronary heart disease and found significant differences in PA, palmitoleic, and OA (18:1).179 Thus, high concentrations of PA, both circulation and adipose tissue, are associated with the incidence of IHD. There was a significant increase in FA uptake and FA oxidation in the heart when the supply of free FA was increased, according to Lopaschuk GD.180 Replacing saturated FA (FA and SA) with plant-based proteins may reduce the risk of myocardial infarction.181
Palmitic Acid Induces Apoptosis in Cardiomyocytes
Palmitic acid induces cardiomyocyte apoptosis by promoting autophagy. Studies have shown that after treating rat cardiomyocytes with PA (0.25 and 0.5 mM) for 18 hours, the number of apoptotic cells and biochemical markers (caspase activation, DNA fragmentation), significantly increased.182 In cardiomyocytes, PA induces apoptosis by promoting the generation of ceramide and activating the mitochondrial apoptosis pathway, leading to the myofibril disintegration.183 In a cohort study involving 4249 participants, the correlation between plasma ceramide (Cer) and sphingomyelin (SM) levels and the risk of sudden heart failure was investigated. The results showed that high levels of PA were associated with a higher risk of heart failure during a median follow-up of 9.4 years.184 Ischemic events are believed to increase the flow of free fatty acids to cardiomyocytes, thereby increasing oxidative stress and causing cardiomyocyte damage.185–188 When the heart is exposed to excessive energy (eg, glucose, free fatty acids, and TG) and growth factors (eg, insulin and leptin) over a long period, it accelerates the development of cardiomyopathy, leading to cardiac hypertrophy and failure. These processes are driven by oxidative stress induced by glucolipotoxicity and become the main drivers of cell apoptosis189 (Figure 3).
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Figure 3 Overview of the mechanism by which palmitic acid promotes ischemic heart disease. PA accelerates progression of induces oxidative stress and autophagic dysregulation, and further triggers cardiomyocyte apoptosis. Additionally, PA promotes cardiomyocyte ferroptosis by reducing the protein expression of Heat Shock Factor 1 and Glutathione Peroxidase 4. These mechanisms collectively drive pathogenesis the onset and development of IHD (↑: increase/activation; ↓: decrease/inhibition).
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Palmitic Acid Promotes Cardiomyocyte Ferroptosis
Ferroptosis is an iron-dependent form of programmed cell death.190 The primary mechanism of ferroptosis is the induction of cell death through the action of divalent iron or lipoxygenases. Additionally, the expression of the antioxidant systems glutathione and glutathione peroxidase 4 (GPX4) is also involved in the process.191 A large body of evidence has shown that ferroptosis is associated with CVD, particularly with ischemia-reperfusion injury and myocardial infarction.192 Using different ferroptosis inhibitors significantly reduced PA-induced death in both H9c2s and primary neonatal rat cardiomyocytes. Specifically, PA promotes ferroptosis by reducing the protein expression of heat shock factor 1 (HSF1) and GPX4, while overexpression of HSF1 and GPX4 effectively prevents PA-induced ferroptosis4 (Figure 3).
Palmitic Acid and Ischemic Stroke
Ischemic stroke has become a major cause of global disease burden due to its high incidence, prevalence, mortality, and disability rates.193 In 2013, an estimated 6.9 million new IS cases occurred globally, with only 18.25 million surviving in good health, 3.32 million deaths, and 65.54 million disabilities.194 Plasma levels of docosahexaenoic acid, LA, arachidonic acid, and PA were measured by gas chromatography in 943 participants from the Framingham Heart Study and 1406 participants from three cities of the Bordeaux Study. The results showed that PA is a risk factor for stroke.195 In a study conducted at the Minneapolis Community Atherosclerosis Risk Center, 3870 white men and women aged 45–64 years (1987–1989) were assessed for plasma cholesterol esters and phospholipid FA, revealing a significant positive correlation between plasma SFAs (particularly PA) and IS.196
Palmitic Acid Promotes Neuroinflammation
Palmitic acid can induce chronic inflammation in both peripheral tissues and the central nervous system, for example, hypothalamic neurons.197–200 In in vitro experiments, PA was found to induce dysfunction in human adipose tissue and soft meningeal artery endothelial cells.201 Researchers found that when Medin (a common amyloid protein) was combined with PA, there was upregulation of IL-6, IL-8, and PAI-1 gene expression in HUVECs, suggesting combined proinflammatory and prothrombotic effects in IS pathogenesis.201,202 Mechanistically, PA promotes TLR4 recruitment to lipid rafts in SH-SY5Y neuroblastoma cells, facilitating TLR4/MYD88/TIRAP complex formation a process potentiated by heme-dependent TLR4 activation.94 PA promoted the upregulation of IL-6 and TNF-α in primary hypothalamic cultures from rats.203 Further studies confirmed that mice fed a high PA diet showed increased hypothalamic cytokine levels, proinflammatory signaling, neuronal death, and impaired leptin and insulin signaling.198,204 Direct intraventricular injection of PA also led to hypothalamic inflammation and insulin resistance.203 PA induces the expression of proinflammatory cytokines in cultured hypothalamic neurons (N42) by increasing ceramide accumulation and lipotoxicity.92 Additionally, PA interacts with LPS to activate microglial cells, upregulating the expression of proinflammatory cytokines via MAPK, NF-κB, and AP-1 signaling pathways, inducing neuroinflammation in HMC3 cells205 (Figure 4).
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Figure 4 Overview of the mechanism by which palmitic acid promotes ischemic stroke. PA exacerbates IS through multi-target mechanisms: (1) Atherogenesis: Accelerates plaque formation via ceramide overproduction and proinflammatory cytokine induction. (2) Neuroinflammation: Triggers CNS inflammatory cascades through microglial TLR/NLRP3 activation and astrocytic metabolic reprogramming. (3) Neuronal Apoptosis: Induces ER stress-autophagy axis dysregulation in neurons. (4) Glial Activation: Directly stimulates microglial inflammatory signaling and astrocytic lipotoxicity. These interconnected pathways collectively drive neurovascular unit dysfunction, culminating in IS progression (↑: increase/activation).
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Palmitic Acid Promotes Apoptosis of Neuronal
The lipotoxicity of PA triggers ER stress and autophagic impairment, leading to an increase in apoptosis and the regulation of neuronal plasticity. High concentrations of PA have been shown to induce ER stress in SH-SY5Y cells and mouse brain cells.206 In SH-SY5Y cells and human glioblastoma cells, PA-induced neurotoxicity and glial cell toxicity, as well as increased oxidative stress in neurons and astrocytes, further promoted cell apoptosis.207 Mechanistic studies reveal that PA upregulates fatty acid transport protein 1 (FATP1) expression, which enhances prefrontal cortical autophagy dysregulation and ER stress while downregulating neuroplasticity markers including synaptophysin (SYN), brain-derived neurotrophic factor (BDNF), and acetylcholine receptors (AChRs).208 High-fat diets containing PA activate the MST1/JNK/Caspase-3 signaling pathway in hippocampal HT22 cells, leading to neuronal apoptosis.209,210 In in vitro experiments, PA significantly increased the autophagic flux in hypothalamic neurons. After PA exposure, the autophagic flux in hypothalamic neurons was suppressed, leading to impaired neuronal autophagy. This autophagic dysfunction was accompanied by changes in lysosomal dynamics, increased Rab7 GTPase activity, ERK phosphorylation, elevated expression of NADPH oxidase 4, and higher levels of inflammation, oxidative stress, and apoptosis in DRG neurons211 (Figure 4).
Palmitic Acid Activates Glial Cells
Glial cells, primarily composed of microglia and astrocytes, PA can activate glial cells. Microglia are the principal FA sensors in the hypothalamus related to neuronal stress and inflammation and are key mediators of the inflammatory response after stroke and brain injury.212 PA promotes inflammation by activating TLR receptors distributed in microglia, and also activates NLRP3 inflammasome by increasing TLR4/MyD88/NF-κB p65 signaling, Long-term activation of hypothalamic microglia inhibits neurogenesis in the medial basal hypothalamus (MBH), and the occurrence of IS further activates microglia and exacerbates disease progression.213,214 Astrocytes are the primary cells responsible for FA oxidation in the brain and play an important role in chronic inflammatory responses associated with obesity and the development of secondary metabolic disorders.215 Although the brain’s energy is primarily provided by glucose PA accumulation in astrocytes activates mitochondrial β-oxidation pathways, generating ATP while inducing proinflammatory activation216 (Figure 4).
Conclusion and Future Directions
Cardiovascular impact of dietary fatty acids exhibits fundamental dichotomy: Saturated fatty acids, particularly PA, promote cardiovascular pathogenesis through pro-inflammatory, dyslipidemic, and endothelial dysfunction pathways. SA as one of the metabolic products of PA, that exhibits neutral metabolic effects. While monounsaturated (eg, oleic acid) and polyunsaturated fatty acids confer cardioprotection. As the most abundant endogenous and dietary SFA, PA serves as a pathophysiological pivot in atherosclerosis development and cerebrovascular complications. Translation of these mechanistic insights into balanced nutritional interventions represents an actionable strategy for global CVD burden reduction.
However, current limitations must be addressed: current evidence exhibits heterogeneity in PA exposure quantification across studies; different organizations, races, and diseases should adopt specific quantitative standards, rather than simply using the same standard for measurement; moreover, most interventional data derive from preclinical models requiring human validation.
To advance this field, future research should prioritize: establish specific quantitative standards for different organizations, races and diseases; elucidate tissue-specific signaling mechanisms (eg, endothelial vs glial PA sensing); develop targeted therapies disrupting PA-induced inflammatory cascades (eg, RGS2 inhibitors); conduct randomized trials testing precision and personalized nutrition approaches for high-risk populations; establish clinical biomarkers quantifying PA’s pathogenic contributions.
Declaration of Generative AI and AI-Assisted Technologies in the Writing Process
During the preparation of this work, the authors used [deep seek] in order to [improve language and readability]. After using this tool, the authors reviewed and edited the content as needed and takes full responsibility for the content of the publication.
Abbreviations
PA, palmitic acid; SFAs, saturated fatty acids; CVD, cardiovascular diseases; AS, atherosclerosis; IHD, ischemic heart disease; IS, ischemic stroke; FA, fatty acid; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ACLY, ATP-citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; ChREBP, carbohydrate response element-binding protein; SREBP-1c, sterol regulatory element binding protein-1c; ER, endoplasmic reticulum; NADH, nicotinamide adenine dinucleotide; FADH2, flavin adenine dinucleotide, reduced; ELOVL1-7, elongation of very long-chain fatty acids 1-7; SA, stearic acid; PE, phosphatidylethanolamine; SCD1, stearoyl coenzyme a desaturase 1; APOM, apolipoprotein M; LDL, low density lipoprotein; VLDL, very low-density lipoprotein; HK2, human kidney-2; AKT, protein kinase B; RGS2, human regulator of G protein signaling 2; IL-6,interleukin-6; CRP, C-reactive protein; TNF-α, tumor necrosis factor-α; Inos, nitric oxide synthase; VSMCs, vascular smooth muscle cells; CYR61, cysteine-rich angiogenic inducer 61; IL-1β, interleukin-1β; MCP-1, monocyte chemoattractant protein-1; NLRP3, NACHT, LRR and PYD domains-containing protein 3; TLR4, Toll-like receptor 4; TLR, toll-like receptors; LPS, lipopolysaccharide; MD2, myeloid differentiation protein 2; pkcζ, atypical protein kinase Czeta; TAK1, transforming growth factor β-activated kinase 1; KLF4, Krüppel-like factor 4; IR, insulin receptors; IGF-1, insulin-like growth factors 1; GLUT4, glucose transporter type 4; IRS1, insulin receptor substrate 1; HAECs, human aortic endothelial cells; MICECs, cardiac microvascular endothelial cells; FABP4, fatty acid‑binding protein 4; OA, oleic acid; LA, linoleic acid; MUFAs, monounsaturated fatty acids; PUFAs, polyunsaturated fatty acids; PGC-1α, Peroxisome proliferator-activated receptor gamma coactivator 1α; UCP2, uncoupling protein 2; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; C/EBP, CCAAT/enhancer binding protein; ATF4, activating transcription factor 4; IRE1-α, inositol-requiring enzyme 1α; TRAF2, tumor necrosis factor receptor-associated factor 2; ASK1, apoptosis signal-regulated kinase 1; JNK, C-jun N-terminal kinase; CHOP, C/EBP homologous protein; T2DM, type 2 diabetes mellitus; ROS, reactive oxygen species; NOX4, calcium/protein kinase Cα/NADH oxidase 4; IRF3, interferon regulator 3; NO, nitric oxide; MAPK, mitogen-activated protein kinase; oxLDL, oxidized LDL; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; 5-HT, 5-hydroxytryptamine; HUVECs, human umbilical vein endothelial Cells; ATMs, M1-like adipose tissue macrophages; PPAR, eroxisome proliferator-activated receptor; GPT-I, carnitine palmitoyl coenzyme A transferase-I; Cer, ceramide; SM, sphingomyelin; GPX4, glutathione peroxidase 4; HSF1, heat shock factor 1; FATP1, fatty acid transport protein 1; SYN, synaptophysin; BDNF, brain-derived neurotrophic factor, AChRs, acetylcholine receptors; MBH, medial basal hypothalamus.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This work was supported by the National Natural Science Foundation of China (32460138); Priority Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University (202101AC070461), and Basic Research Program of Yunnan Province Science and Technology Department (202301AT070083).
Disclosure
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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