To discuss the recent developments in structure, function and physiology of lipoprotein lipase (LpL) and the regulators of LpL, which are being targeted for therapy.
Recent studies have revealed the ...long elusive crystal structure of LpL and its interaction with glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1). New light has been shed on LpL being active as a monomer, which brings into questions previous thinking that LpL inhibitors like angiopoietin-like 4 (ANGPTL4) and stabilizers like LMF1 work on disrupting or maintaining LpL in dimer form. There is increasing pharmaceutical interest in developing targets to block LpL inhibitors like ANGPTL3. Other approaches to reducing circulating triglyceride levels have been using an apoC2 mimetic and reducing apoC3.
Lipolysis of triglyceride-rich lipoproteins by LpL is a central event in lipid metabolism, releasing fatty acids for uptake by tissues and generating low-density lipoprotein and expanding high-density lipoprotein. Recent mechanistic insights into the structure and function of LpL have added to our understanding of triglyceride metabolism. This has also led to heightened interest in targeting its posttranslational regulators, which can be the next generation of lipid-lowering agents used to prevent hypertriglyceridemic pancreatitis and, hopefully, cardiovascular disease.
Despite the decades-old knowledge that diabetes mellitus is a major risk factor for cardiovascular disease, the reasons for this association are only partially understood. While this association is ...true for both type 1 and type 2 diabetes, different pathophysiological processes may be responsible. Lipids and other risk factors are indeed important, whereas the role of glucose is less clear. This lack of clarity stems from clinical trials that do not unambiguously show that intensive glycemic control reduces cardiovascular events. Animal models have provided mechanisms that link diabetes to increased atherosclerosis, and evidence consistent with the importance of factors beyond hyperglycemia has emerged. We review clinical, pathological, and animal studies exploring the pathogenesis of atherosclerosis in humans living with diabetes and in mouse models of diabetes. An increased effort to identify risk factors beyond glucose is now needed to prevent the increased cardiovascular disease risk associated with diabetes.
Diabetes increases cardiovascular disease risk, but the reasons for the association are not fully understood. Here, Eckel et al. review clinical and animal studies that explore the pathogenesis of atherosclerosis in the diabetes context. They discuss the need to identify and understand risk factors beyond glucose in order to prevent increased cardiovascular disease risk in diabetes.
Lipid Use and Misuse by the Heart Schulze, P Christian; Drosatos, Konstantinos; Goldberg, Ira J
Circulation research,
2016-May-27, Letnik:
118, Številka:
11
Journal Article
Recenzirano
Odprti dostop
The heart utilizes large amounts of fatty acids as energy providing substrates. The physiological balance of lipid uptake and oxidation prevents accumulation of excess lipids. Several processes that ...affect cardiac function, including ischemia, obesity, diabetes mellitus, sepsis, and most forms of heart failure lead to altered fatty acid oxidation and often also to the accumulation of lipids. There is now mounting evidence associating certain species of these lipids with cardiac lipotoxicity and subsequent myocardial dysfunction. Experimental and clinical data are discussed and paths to reduction of toxic lipids as a means to improve cardiac function are suggested.
Cholesterol is not the only lipid that causes heart disease. Triglyceride supplies the heart and skeletal muscles with highly efficient fuel and allows for the storage of excess calories in adipose ...tissue. Failure to transport, acquire, and use triglyceride leads to energy deficiency and even death. However, overabundance of triglyceride can damage and impair tissues. Circulating lipoprotein-associated triglycerides are lipolyzed by lipoprotein lipase (LpL) and hepatic triglyceride lipase. We inhibited these enzymes and showed that LpL inhibition reduces high-density lipoprotein cholesterol by >50%, and hepatic triglyceride lipase inhibition shifts low-density lipoprotein to larger, more buoyant particles. Genetic variations that reduce LpL activity correlate with increased cardiovascular risk. In contrast, macrophage LpL deficiency reduces macrophage function and atherosclerosis. Therefore, muscle and macrophage LpL have opposite effects on atherosclerosis. With models of atherosclerosis regression that we used to study diabetes mellitus, we are now examining whether triglyceride-rich lipoproteins or their hydrolysis by LpL affect the biology of established plaques. Following our focus on triglyceride metabolism led us to show that heart-specific LpL hydrolysis of triglyceride allows optimal supply of fatty acids to the heart. In contrast, cardiomyocyte LpL overexpression and excess lipid uptake cause lipotoxic heart failure. We are now studying whether interrupting pathways for lipid uptake might prevent or treat some forms of heart failure.
CD36 is a multifunctional immuno-metabolic receptor with many ligands. One of its physiological functions in the heart is the high-affinity uptake of long-chain fatty acids (FAs) from albumin and ...triglyceride rich lipoproteins. CD36 deletion markedly reduces myocardial FA uptake in rodents and humans. The protein is expressed on endothelial cells and cardiomyocytes and at both sites is likely to contribute to FA uptake by the myocardium. CD36 also transduces intracellular signaling events that influence how the FA is utilized and mediate metabolic effects of FA in the heart. CD36 transduced signaling regulates AMPK activation in a way that adjusts oxidation to FA uptake. It also impacts remodeling of myocardial phospholipids and eicosanoid production, effects exerted via influencing intracellular calcium (iCa2+) and the activation of phospholipases. Under excessive FA supply CD36 contributes to lipid accumulation, inflammation and dysfunction. However, it is also important for myocardial repair after injury via its contribution to immune cell clearance of apoptotic cells. This review describes recent progress regarding the multiple actions of CD36 in the heart and highlights those areas requiring future investigation. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
•Importance of CD36 for cardiac metabolic flexibility•CD36 maintains AMPK quiescent.•Fatty acid uptake signals to upregulate fatty acid oxidation.•Cytosolic calcium and myocardial phospholipid metabolism•CD36 contributes to inflammation and its resolution in the heart.
Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large ...cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.
Addressing dyslipidemic risk beyond LDL-cholesterol Tall, Alan R; Thomas, David G; Gonzalez-Cabodevilla, Ainara G ...
The Journal of clinical investigation,
01/2022, Letnik:
132, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated ...levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.
Diabetes is now a pandemic disease. Moreover, a large number of people with prediabetes are at risk for developing frank diabetes worldwide. Both type 1 and type 2 diabetes increase the risk of ...atherosclerotic cardiovascular disease (CVD). Even with statin treatment to lower LDL cholesterol, patients with diabetes have a high residual CVD risk. Factors mediating the residual risk are incompletely characterized. An attractive hypothesis is that remnant lipoprotein particles (RLPs), derived by lipolysis from VLDL and chylomicrons, contribute to this residual risk. RLPs constitute a heterogeneous population of lipoprotein particles, varying markedly in size and composition. Although a universally accepted definition is lacking, for the purpose of this review we define RLPs as postlipolytic partially triglyceride-depleted particles derived from chylomicrons and VLDL that are relatively enriched in cholesteryl esters and apolipoprotein (apo)E. RLPs derived from chylomicrons contain apoB48, while those derived from VLDL contain apoB100. Clarity as to the role of RLPs in CVD risk is hampered by lack of a widely accepted definition and a paucity of adequate methods for their accurate and precise quantification. New specific methods for RLP quantification would greatly improve our understanding of their biology and role in promoting atherosclerosis in diabetes and other disorders.
The heart has both the greatest caloric needs and the most robust oxidation of fatty acids (FAs). Under pathological conditions such as obesity and type 2 diabetes, cardiac uptake and oxidation are ...not balanced and hearts accumulate lipid potentially leading to cardiac lipotoxicity. We will first review the pathways utilized by the heart to acquire FAs from the circulation and to store triglyceride intracellularly. Then we will describe mouse models in which excess lipid accumulation causes heart dysfunction and experiments performed to alleviate this toxicity. Finally, the known relationships between heart lipid metabolism and dysfunction in humans will be summarized.
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