The role of lipotoxicity in cardiovascular disease : Emergency and Critical Care Medicine

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The role of lipotoxicity in cardiovascular disease

Li, Chuanbaoa,b,c; Liu, Huiruoa,b,c; Xu, Fenga,b,c; Chen, Yuguoa,b,c,∗

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Emergency and Critical Care Medicine 2(4):p 214-218, December 2022. | DOI: 10.1097/EC9.0000000000000024
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Abstract

Introduction

Lipids are crucial for storing and supplying energy to the body and are important structural components of biofilms.[1] Lipid deposition often occurs in patients with diabetes, obesity, septicemia, and metabolic syndrome among others. These conditions have been found to be closely correlated with reduced oxidation of fatty acids (FAs).[2,3] As the pump of the circulatory system, the heart consumes a large amount of energy to satisfy its contractile demands. More than 70% of the substrate that is oxidized to promote adenosine triphosphate (ATP) comes from FAs. This is considered the primary energy source for the myocardia, while the remainder originates from glucose, lactic acid, acetone bodies, or amino acids.[4]

Tight coupling between the uptake and utilization of FAs prevents excessive lipid storage in cardiomyocytes. Excessive lipids can lead to cardiac fibrosis, cardiomyocyte apoptosis, myocardial remodeling, and subsequent heart failure. This type of heart failure is termed lipotoxic cardiomyopathy.[5,6] FA accumulates in the mitochondria, leading to mitochondrial dysfunction.[7,8] However, the reversal of this dysfunction suggests that lipotoxic cardiomyopathy may be a reversible disease.[9,10] Preventing or reducing excess lipids can improve the cardiac metabolism and function. Here, we briefly summarize the research on toxic lipids and review the recent progress in lipid therapy. We explore updated methods to improve cardiac function by reducing toxic lipids (Fig. 1).

F1
Figure 1:
Graphical summary. ACStg, ACSL1 transgenic; CTRP9, C1q/TNF-related Protein 9; DG, diacylglycerol; FFA, free fatty acid; HFD, high-fat diet; HFSD, high fat high sucrose diet; PPARα, peroxisome proliferator-activated receptor-α; STZ, streptozocin; TG, triglyceride.

Lipids in cardiac toxicity

Myocardial lipid content is positively correlated with circulating free fatty acids (FFAs).[11] Induced expression of CD36, a fatty acid translocation enzyme, is associated with the increased uptake of FFA in myocardial cells. Overexpression of miR-320 is sufficient to induce CD36 in both normal and diabetic conditions. However it only worsens cardiac function in diabetes.[12] FA upregulates glycogen synthase kinase-3α (GSK-3α),[13] which in turn phosphorylates peroxisome proliferator-activated receptor (PPAR)α at Ser280. This modification selectively enhances the transcription of genes involved in FA uptake and storage, but not oxidation. This modification is considered to be fundamental to lipotoxic cardiomyopathy in obesity. Long-term (>8 h) exposure of neonatal rat ventricular myocytes to palmitate enhanced reactive oxygen species (ROS) production,[14] accompanied by loss of mitochondrial network, was associated with AKAP121-mediated phosphorylation of dynamin-related protein 1 and optic atrophy1 hydrolysis. Clearance of mitochondrial ROS reversed mitochondrial morphological changes. Patients with right heart failure induced by pulmonary hypertension show increased long-chain fatty acids (LCFAs) and decreased long-chain acylcarnitine levels in the right ventricle.[15] Acyl-CoA synthase 1 (ACSL1) promotes LCFA uptake and CoA activation.[16] Cardiac-restricted overexpression of ACSL1 alleviates transverse aortic constriction-induced cardiac hypertrophy and dysfunction in mice.[17] Knocking down the genes of acetyl-CoA carboxylase 2 (ACC2),[18] eliminating the inhibition of LCFA to the mitochondria and increasing FFA oxidation, ultimately prevents palmitate-induced mitochondrial dysfunction and cardiomyocyte death in vitro.

In addition to providing energy for mitochondrial oxidation, a small amount of FA obtained by cardiomyocytes is synthesized into triglyceride (TG) and stored in lipid droplets in the cytoplasm. Studies have shown that diacylglycerol (DG) stimulates the exocrine secretion of calcium-permeable transient receptor potential canonical 6 by targeting the C1 domain of MUNC13-2. It then mediates stress-induced cardiac remodeling.[19] Thus, DAGT1–/– rats show myocardial lipotoxicity.[20] Therefore, the temporary esterification of toxic lipid into TG can be regarded as a self-protective mechanism of the heart. However, certain studies have pointed out that the accumulation of intracellular TG caused by the deficiency of fatty adipose triglyceride lipase (ATGL) could lead to diffuse coronary atherosclerosis stenosis. Vascular smooth muscle and endothelial cells with extra TG often present vulnerable or pro-inflammatory phenotypes.[21,22] ATGL–/– mice exhibit severe myocardial steatosis, resulting in premature death.[23,24] In contrast, in catecholamine-induced myocardial injury models, inhibition of ATGL reduced the expression of α-1 type I collagen and α-1 type III collagen genes, thereby reducing myocardial apoptosis and fibrosis.[25] In addition to lipid content, lipid droplet size was also found to be associated with toxicity. Overexpression of PPARγ in PPARα–/– mice improved cardiac function without changing intracellular lipid concentrations. However, it increased lipid droplet size.[26] Further analysis indicated that large droplets reduced the total surface area and reflected more inert lipid storage, while smaller droplets may be more likely to trigger harmful molecular pathways.[27]

Ceramides are regulated by ceramidase.[28,29] Elevated cardiac ceramides have been observed in various obesity models.[30–32] Ceramide disrupts insulin-dependent Akt phosphorylation and the expression of key metabolic enzymes. This includes glucose transporter 4 (GLUT4), AMP-activated protein kinase (AMPK), PPARα, CD36, and PPARγ, through the activation of protein phosphatase 2A (PP2A).[33] Moreover, it can also increase the expression of mitochondrial autophagy-related proteins. Adiponectin regulates the activity of ceramidase, and its overexpression reduces caspase-8-mediated apoptosis.[34,35] Inhibition of serine palmityl transferase by myristin blocks de novo synthesis of ceramide and improves cardiac systolic function in a mouse model of lipotoxic cardiomyopathy.[36] Cardiac dysfunction in ob/ob mice might be prevented by lowering ceramide levels when stearyl CoA desaturase is inhibited.[37] Ceramide can exert its cardiotoxic effects by driving insulin resistance, oxidative stress, increased autophagy, and mitochondrial dysfunction (Fig. 2).

F2
Figure 2:
Depiction of lipids metabolism in myocardium. ATGL, adipose triglyceride lipase; DG, diacylglycerol; DGAT1, diacylglyceryl transferase 1; FFA, free fatty acid; TG, triglyceride.

Animal models of cardiac lipotoxicity

ACSL1 converts free LCFAs into fatty acyl-CoA esters, thereby playing a key role in fatty acid degradation. In a mouse model with low-level overexpression of ACSL1 driven by the cardiomyocyte-specific α-MHC (myosin heavy chain) promoter (ACSL1 transgenic [ACStg] mice),[38] myocardial ceramides and diglycerides (without TGs) were significantly increased at 12 weeks. They subsequently decreased arterial blood pressure and increased brain natriuretic peptide secretion, which implicated systolic dysfunction. Compared with WT mice, CTRP9–/– mice fed a continuous high-fat diet (HFD) showed more serious myocardial hypertrophy and fibrosis by the age of 26 weeks.[39] This tendency is consistent with the accumulation of FA synthase, TG, and ceramides in cardiomyocytes. As PPARα positively regulates FA uptake and oxidation, PPARα–/– mice show decreased expression of ATGL and CPT-1[40] with elevated mRNA levels of GLUT4.[41] These results suggest that PPARα–/– changes the primary source of ATP from FA oxidation to glycolysis. This is further confirmed by myocardial lipotoxicity in PPARα-CKO mice.[42] Knocking out downstream genes of PPARα, such as CPT-1,[43,44] ATGL[45–47] or DGAT,[48–50] also resulted in lipid-mediated cardiac dysfunction in mice. In addition, PPARγ-overexpressing mice had larger lipid droplet sizes in the myocardium. This corresponded to improved cardiac contractile function.[51] Other less commonly used gene-deficient models, such as Pgrmc1-KO,[52] TaZ-KO,[53] Arnt-KO,[54] FATP-overexpressed,[55] and FUNdC1-KO,[56] also showed myocardial lipotoxicity.

Dietary intervention is the most common method used to construct lipotoxic mouse models. C57BL/6 mice showed glucose intolerance as early as 24 hours after initiating a HFD.[57] When Wistar rats were fed a HFD (33.5% fat) for 6 weeks, they showed myocardial hypertrophy and interstitial fibrosis despite no significant changes in cardiac function or blood pressure.[58] Mouse models such as db/db and ob/ob mice are examples of spontaneous lipotoxicity.[59] Leptin deficiency inactivates satiety signaling and causes gluttony in mice. This leads to obesity-mediated lipotoxic cardiomyopathy. Six-month-old db/db mice exhibited elevated levels of serum lipids (total Cholesterol, TG, and low density lipoprotein), showing irregularly swollen cardiac myocytes with high lipid droplet accumulation.[60] Under HFD for 4 weeks, significant reductions in left ventricular pressure and coronary blood flow were observed. Rats were administered an intraperitoneal injection of streptozocin (STZ) (15 mg/kg) for 12 weeks after 4 weeks of HFD,[61] with increasing serum TG and NEFA. Oil red O staining suggested accumulation of neutral lipid in the myocardium, and echocardiography showed impairment of the left ventricular ejection fraction.

Rats fed a high-glucose-high-fat diet showed mild left ventricular hypertrophy, impaired longitudinal tension, and other pre-manifestations of diabetic cardiomyopathy at 10 weeks. However, the overall diastolic and contractile functions of the myocardium were retained.[38] With the prolongation of the modeling process, the ceramide and diglyceride content in the myocardium significantly increased, followed by pathological hypertrophy and local myocardial function.

Lipotoxicity-associated cardiopathy

Lipid storage at various locations may have different toxic effects on the cardiovascular system. Accumulation of intracellular FA and TG promotes endoplasmic reticulum stress, mitochondrial uncoupling, cell apoptosis, and ultimately an inflammatory response.[62] Epicardial adipose tissue (EAT) and myocardial steatosis are associated with atrial fibrillation and ventricular dysfunction.[63,64] EAT directly contacts the myocardium and coronary arteries and may regulate the myocardium through the parocrine signaling pathway.[65] Several studies have indicated that EAT accumulation plays a promoting role in coronary endothelial cell dysfunction.[66] There is no direct intervention for intracellular and epicardial lipid accumulation. Thus, we are attempting to regulate these two types of lipids by lowering the serum lipid levels. However, the accumulation of EAT was related to poor hemodynamics and metabolic rates in heart failure with preserved ejection fraction and lower values in HFrEF.[67] Both insulin resistance and hyperglycemia are closely related to lipotoxic injury in cardiomyocytes.[68] Recipients after heart transplantation with diabetes were more likely to have earlier cardiac lipid deposition at 3 months.[69] Mechanical unloading after implantation of left ventricular assist devices corrects systemic and local metabolic disorders in advanced heart failure. It improves insulin signaling and reduces toxic lipid intermediates.[70] Right heart failure is the leading cause of death due to pulmonary hypertension and is associated with cardiac steatosis and lipotoxicity.[71] Studies have shown that circulating FFAs and long-chain acylcarnitine levels are significantly elevated in patients with pulmonary arterial hypertension (PAH). This is associated with an abnormal accumulation of TGs and ceramides in the myocardium. In some cases,[72,73] patients with pulmonary hypertension show elevated right ventricular lipids, while the structure and function are generally normal. The presence of myocardial lipid accumulation in the subclinical stage suggests that it may be one of the causes of right heart failure.

Conclusion

The importance of lipid toxicity as a cause or accessory to human heart failure is gradually being accepted. Due to the lack of diagnostic methods to evaluate lipotoxic cardiomyopathy in clinical practice, most studies take place in animal models. Therefore, strengthening the study of the relationship between lipids and the myocardium is of great significance for the diagnosis and treatment of cardiac diseases.

Conflict of interest statement

Yuguo Chen is the Editor-in-Chief of Emergency and Critical Care Medicine, and Feng Xu is an Editorial Board member of Emergency and Critical Care Medicine. The article was subject to the journal’s standard procedures, with peer review handled independently of the Editor-in-Chief, this Editorial Board member, and their research groups. The authors declare no conflicts of interest.

Author contributions

Li C and Chen Y participated in research design. Li C, Liu H, and Xu F participated in writing the paper. Li C participated in the performance of the research. Chen Y contributed to new reagents and analytic tools. Li C and Liu H participated in data analysis. All authors read and approved the final manuscript.

Funding

This work was supported by grants to C.B.L. from the National Natural Science Foundation of China (82070388), Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), and the National Natural Science Foundation of Shandong Province (ZR2020MH035).

Ethical approval of studies and informed consent

Not applicable.

Acknowledgements

We wish to thank our colleagues from the Emergency Department of Qilu Hospital of Shandong University for their valuable comments on the manuscript.

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    Keywords:

    Cardiovascular disease; Ceramide; Free fatty acid; Lipotoxicity; Triglyceride

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