Lysosomal acid lipase and lipid metabolism: new mechanisms, new questions, and new therapies

Ren

et al. 2020

Sci Rep

Autophagy, an integral part of the waste recycling process, plays an important role in cellular physiology and pathophysiology. Impaired autophagic flux causes ectopic lipid deposition, which is defined as the accumulation of lipids in non-adipose tissue. Ectopic lipid accumulation is observed in patients with cardiometabolic syndrome, including obesity, diabetes, insulin resistance, and cardiovascular complications. Metformin is the first line of treatment for type 2 diabetes, and one of the underlying mechanisms for the anti-diabetic effect of metformin is mediated by the stimulation of AMP-activated protein kinase (AMPK). Because the activation of AMPK is crucial for the initiation of autophagy, we hypothesize that metformin reduces the accumulation of lipid droplets by increasing autophagic flux in vascular endothelial cells. Incubation of vascular endothelial cells with saturated fatty acid (SFA) increased the accumulation of lipid droplets and impaired autophagic flux. We observed that the accumulation of lipid droplets was reduced, and the autophagic flux was enhanced by treatment with metformin. The knock-down of AMPKα by using siRNA blunted the effect of metformin. Furthermore, treatment with SFA or inhibition of autophagy increased leukocyte adhesion, whereas treatment with metformin decreased the SfA-induced leukocyte adhesion. The results suggest a novel mechanism by which metformin protects vascular endothelium from SFA-induced ectopic lipid accumulation and pro-inflammatory responses. In conclusion, improving autophagic flux may be a therapeutic strategy to protect endothelial function from dyslipidemia and diabetic complications. Abbreviations SFA Saturated fatty acid T2DM Type 2 diabetes mellitus AMPK AMP-activated protein kinase LC3 Microtubule-associated protein 1A/1B-light chain 3 ER Endoplasmic reticulum eNOS Endothelial nitric oxide synthase ULK1 Unc51-like kinase 1 CPT1 Carnitine palmitoyltransferase 1 LD Lipid droplet AICAR 5-Aminoimidazole-4-carboxamide 1-β-d-ribofuranoside, Acadesine, N 1-(β-d-ribofuranosyl)-5aminoimidazole-4-carboxamide

Section: Resultsmentioning

confidence: 99%

Metformin reduces saturated fatty acid-induced lipid accumulation and inflammatory response by restoration of autophagic flux in endothelial cells

Ren

et al. 2020

Sci Rep

“… Fatty acids contained in triacylglycerol-rich chylomicrons and very-low-density lipoproteins (VLDL) or cholesteryl ester-rich low-density lipoproteins (LDL) can be endocytosed via the actions of receptors including VLDL-receptor (VLDLr), LDL-receptor (LDLr), lipolysis-stimulated receptor (LSR) [ 48 ], low-density lipoprotein receptor-related protein 1 (LPR1) [ 49 ], or SR-B1 [ 50 ]. These fatty acid-rich particles then enter the endosomal-lysosomal pathway involving lysosomal acid lipases to liberate free fatty acids [ 51 ]. …”

Section: Tumor Fatty Acid Metabolism Pathways and Their Role In Cancementioning

confidence: 99%

The diversity and breadth of cancer cell fatty acid metabolism

2021

Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and cellular homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation and cell-extrinsic influences, including growth factor and nutrient availability. Alongside glucose and amino acid metabolism, fatty acid metabolism supports tumorigenesis and disease progression through a range of processes including membrane biosynthesis, energy storage and production, and generation of signaling intermediates. Here, we highlight the complexity of cellular fatty acid metabolism in cancer, the various inputs and outputs of the intracellular free fatty acid pool, and the numerous ways that these pathways influence disease behavior.

“…Lysosomal acid lipase is the main enzyme that hydrolyzes low-density lipoproteins and the modified forms of low-density lipoproteins, playing a pivotal role in lipid decomposition and prevention of excessive lipid accumulation 144 . Upon the development of atherosclerosis, excessive accumulation of free cholesterol leads to the suppression of lysosomal acid lipase activity and the accumulation of cholesterol esters in lysosomes 145 . In addition, deficiency of primary LAMP-2 is associated with the occurrence of Danon disease 25 , as evidenced by the pathological characteristics of massive autophagosome deposition in cardiomyocytes and skeletal muscle cells 146 , 147 .…”

Section: Lysosomes and Various Diseasesmentioning

confidence: 99%

Lysosomal quality control of cell fate: a novel therapeutic target for human diseases

Zhu

Yao

et al. 2020

Cell Death Dis

In eukaryotic cells, lysosomes are digestive centers where biological macromolecules are degraded by phagocytosis and autophagy, thereby maintaining cellular self-renewal capacity and energy supply. Lysosomes also serve as signaling hubs to monitor the intracellular levels of nutrients and energy by acting as platforms for the assembly of multiple signaling pathways, such as mammalian target of rapamycin complex 1 (mTORC1) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK). The structural integrity and functional balance of lysosomes are essential for cell function and viability. In fact, lysosomal damage not only disrupts intracellular clearance but also results in the leakage of multiple contents, which pose great threats to the cell by triggering cell death pathways, including apoptosis, necroptosis, pyroptosis, and ferroptosis. The collapse of lysosomal homeostasis is reportedly critical for the pathogenesis and development of various diseases, such as tumors, neurodegenerative diseases, cardiovascular diseases, and inflammatory diseases. Lysosomal quality control (LQC), comprising lysosomal repair, lysophagy, and lysosomal regeneration, is rapidly initiated in response to lysosomal damage to maintain lysosomal structural integrity and functional homeostasis. LQC may be a novel but pivotal target for disease treatment because of its indispensable role in maintaining intracellular homeostasis and cell fate.