Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases
Abstract
:1. Introduction
2. Lipids in Eukaryotic Cells
2.1. Fatty Acids and Cholesterol—Essential and Toxic
2.2. Lipid Droplets—Storage of Neutral Lipids
3. Lipophagy and Lipolysis—Two Pathways that Play a Crucial Role in Lipid Metabolism
3.1. Catabolism of Lipid Droplets
3.2. Energy Release from Fatty Acids
3.3. Transcriptional Regulation of Lipophagy, Lipolysis and Lipid Metabolism
4. Lipid Metabolism and Diseases
4.1. Characterization of Lipid Storage Diseases and Lipid Metabolism Diseases
4.2. Dysregulation of Autophagy or Lipolysis in Diseases
4.3. Secondary Lipid Accumulation in Lysosomal Storage Diseases
4.4. Consequences of Secondary Lipid Storage
4.5. mTOR–TFEB Signaling Pathway and Dysregulation of Autophagy in Lipid Storage Diseases
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ADRP | adipophilin |
AFSM | autofluorescent storage material |
AMPK | AMP-activated protein kinase |
ARF | ADP-ribosylation factor |
ATGL | adipose triglyceride lipase |
BMP | bis(monoacylglycero)phosphate |
CaMKKβ | calcium/calmodulin-dependent protein kinase β |
CAV | caveolin |
CGI-58 | comparative gene identification-58 |
CLEAR | coordinated lysosomal expression and regulation |
CLN | ceroid lipofuscinosis, neuronal |
CMA | chaperon-mediated autophagy |
CoA | coenzyme A |
COP | coat protein |
CREB | cAMP response element-binding |
CTX | cerebrotendinous xanthomatosis |
DAG | diacylglycerols |
ER | endoplasmic reticulum |
ERK2 | extracellular signal-regulated kinase 2 |
ES | sterol ester |
FA | fatty acid |
FAD | flavin-adenine dinucleotide |
FGE | formylglycine-generating enzyme |
FOXO | forkhead homeobox type O |
FXR | farnesoid X receptor |
Hsc70 | heat shock cognate 70 |
HSL | hormone-sensitive lipase |
LAL | lysosomal acid lipase |
LAMP2A | lysosome-associated membrane protein 2A |
LC3 | light chain 3 |
LD | lipid droplet |
LDL | low-density lipoprotein |
LINCL | late infantile neuronal ceroid lipofuscinosis |
LIR | LC3 interaction region |
LSD | lysosomal storage disease |
MAG | monoacylglycerol |
MAPK | mitogen-activated protein kinase |
MGL | monoglyceride lipase |
MiT | microphthalmia |
MLD | metachromatic leukodystrophy |
MPS | mucopolysaccharidosis |
MSD | multiple sulfatase deficiency |
mTOR | mechanistic target of rapamycin |
mTORC1 | mechanistic target of rapamycin complex 1 |
NCoR1 | nuclear receptor co-repressor 1 |
OSBP | oxysterol binding protein |
PAT | PLIN/ADRP/TIP47 |
PC | phosphatidylcholine |
PE | phosphatidylethanolamine |
PGC1α | peroxisome proliferator-activated receptor gamma coactivator 1α |
PI | phosphatidylinositol |
PI3K | phosphatidylinositol 3-kinase |
PI3P | phosphatidylinositol 3-phosphate |
PKA | protein kinase A |
PLIN | perilipin |
PPAR1α | peroxisome proliferator activated receptor 1α |
PPARGC1α | peroxisome proliferator-activated receptor gamma coactivator 1α |
PS | phosphatidylserine |
RBC | red blood cell |
SM | sphingomyelin |
SNARE | soluble N-ethylmaleimide-sensitive factor attachment receptor |
TAG | triacylglycerol |
TFE3 | transcription factor E3 |
TFEB | transcription factor EB |
TIP47 | tail-interacting protein of 47 kDa |
TRPML1 | mucolipin transient receptor potential 1 |
VLDL | very low-density lipoprotein |
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Disease | Gene Deficient Enzyme/Protein | Accumulated Products | Symptoms | Perturbations in Autophagy/Lipophagy/Lipolysis | Reference |
---|---|---|---|---|---|
Lysosomal storage diseases | |||||
Lipid storage diseases | |||||
Sphingolipidoses | |||||
Niemann–Pick disease types A and B | SMPD1 sphingomyelinase | Sphingomyelin in brain and red blood cells (RBCs) | Hepatosplenomegaly, psychomotor regression, clumsiness and difficulty walking, dystonia, sleep disturbances, difficulty swallowing and eating, recurrent pneumonia, thrombocytopenia, a cherry-red spot inside the eye, frequent respiratory infections, slow mineralization of bone | Impaired autolysosomal clearance; formation of late endosome/lysosome (LE/LY)-like storage organelles (LSOs) and the misdirection of lipids to the LSOs; defect in autophagosome maturation; accumulation of autophagosomes | [74,75,76,77] |
Niemann–Pick disease type C | NPC1 or NPC2 intracellular cholesterol transporters located within lysosomal and endosomal membranes (NPC1) or inside lysosomes (NPC2) | Free cholesterol, sphingomyelin and glycosphingolipid storage in lysosomes or late endosomes | Hepatosplenomegaly, problems with speech and swallowing, dementia, seizures, ataxia, vertical supranuclear gaze palsy, dystonia, severe liver disease, interstitial lung disease | Defective amphisome formation; impaired maturation of autophagosomes; accumulation of autophagosomes and autolysosomes | [78,79,80,81,82] |
Fabry disease | GLA α-galactosidase A | Glycolipids, particularly ceramide trihexoside, in brain, heart and kidney | Episodes of pain (particularly acroparesthesias), angiokeratomas, hypohidrosis, corneal opacity or corneal verticillate, problems with the gastrointestinal system, tinnitus, hearing loss, kidney damage, heart attack, stroke | Impairment of the autophagic pathway | [83,84,85,86] |
Krabbe disease (globoid cell leukodystrophy) | GALC galactocerebrosidase | Glycolipids, particularly galactocerebroside, in oligodendrocytes | Irritability, muscle weakness, feeding difficulties, stiff posture, delayed mental and physical development, spasticity, hypertonia, blindness, hyperreflexia, deafness, neurodegeneration (leading to death) | Impairment of autophagy; lysosomal dysfunction; partial blocking and saturation of the autophagy flux | [87,88,89,90] |
Gaucher disease | GBA glucocerebrosidase | Glucocerebrosides in RBCs, liver and spleen | Hepatosplenomegaly, pancytopenia, Erlenmeyer flask deformity, anemia, lung disease, bone abnormalities such as bone pain, fractures, arthritis | Impaired autophagosome maturation; accumulation of autophagosomes; autophagy block | [91,92,93] |
Tay–Sachs disease | HEXA β-hexosaminidase A | GM2 gangliosides in neurons | Neurodegeneration, seizures, vision and hearing loss, cherry-red spot, muscle weakness, ataxia, intellectual disability, paralysis, early death | Altered lipid trafficking; impaired autophagy | [94,95,96,97] |
Tay–Sachs Disease, AB Variant (AB-variant GM2) | GM2A GM2 ganglioside activator | GM2 ganglioside in neurons in the brain and spinal cord | Psychomotor deterioration, seizures, vision and hearing loss, intellectual disability, paralysis, cherry-red spot, early death | Impaired autophagy | [95,98,99] |
Metachromatic leukodystrophy (MLD) | ASA or PSAP arylsulfatase A or prosaposin | Sulfatide compounds in neural tissue | Demyelination in central and peripheral nervous systems (peripheral neuropathy, mental retardation, motor dysfunction, ataxia, hyporeflexia), seizures, incontinence, paralysis, inability to speak, blindness, hearing loss | Affected trafficking due to altered chain length of the lipids; defective autophagosome–lysosome fusion, impaired autophagy | [100,101,102,103] |
Sandhoff disease | HEXB β-hexosaminidase A and β-hexosaminidase B | GM2 ganglioside in neurons of the brain and spinal cord | Progressive nervous system deterioration, muscle weakness, ataxia, speech problems, mental retardation, blindness, seizures, spasticity, macrocephaly, cherry-red spots in the eyes, frequent respiratory infections, doll-like facial appearance, hepatosplenomegaly | Disruption of autophagy, aberrant lysosomal–autophagic turnover | [104,105,106,107] |
Multiple sulfatase deficiency | SUMF1 formylglycine-generating enzyme (FGE) | Sulfatides, sulfated glycosaminoglycans, sphingolipids and steroid sulfates in tissues | Leukodystrophy, movement problems, seizures, developmental delay, slow growth, ichthyosis, hypertrichosis, skeletal abnormalities (scoliosis, joint stiffness, dysostosis multiplex), hypotonia, coarse facial features, mild deafness, hepatomegaly, progressive neurologic deterioration, hydrocephalus | Accumulation of autophagosomes, defective autophagosome–lysosome fusion | [108,109,110] |
GM1 gangliosidosis | GLB1 β-galactosidase | GM1 ganglioside in tissues and organs, particularly in the brain | Hepatosplenomegaly, skeletal abnormalities, seizures, profound intellectual disability, cherry-red spot, gingival hypertrophy, cardiomyopathy, dysostosis multiplex, coarsened facial features | Accumulation of autophagosomes, impaired lysosomal flux | [101,111,112] |
Schindler disease | NAGA α-N-acetylgalactosaminidase | Glycosphingolipids, glycoproteins and oligosaccharides with terminal or preterminal N-acetylgalactosaminyl residues in the lysosomes of most tissues | Developmental regression, blindness, seizures, loss of awareness of surroundings, unresponsive, cognitive impairment, sensorineural hearing loss, weakness and loss of sensation, angiokeratomas | No data | [113] |
Sea-blue histiocytosis (inherited lipemic splenomegaly) | APOE apolipoprotein E | Cholesterol, triglycerides and beta-very-low-density lipoproteins (beta-VLDLs) in the blood; glycosphingolipids, particularly sphingomyelins in the histocytes | Hypertriglyceridemia, splenomegaly, liver function abnormalities, heart disease, sea-blue histiocytes in many organs (bone marrow, liver and spleen) | No data | [114] |
Neuronal ceroid lipofuscinosis | |||||
Batten disease (juvenile neuronal ceroid lipofuscinosis, CLN3 disease) | CLN3 battenin, hydrophobic transmembrane protein involved in lysosomal function | Lysosomal autofluorescent storage material (AFSM) in the cells of the brain, central nervous system, and retina in the eye | Progressive blindness, seizures, mental and cognitive decline, dementia, speech and motor skills problems, premature death | Disruption of autophagy, vacuole maturation and impaired mitophagy; impaired autophagic clearance, defective autophagosome maturation | [115,116,117,118] |
Jansky–Bielschowsky disease (late infantile neuronal ceroid lipofuscinosis, LINCL, CLN2 disease) | TPP1 tripeptidyl-peptidase 1 | Lipopigments in neurons, primarily in the cerebral and cerebellar cortices | Epilepsy, ataxia, myoclonus, vision loss, speech and motor skills problems (e.g., sitting and walking), developmental regression, intellectual disability, behavioral problems | Reduction in autophagic flux, inhibition of autophagosome formation, reduction in autophagosomes and autophagic degradation | [119,120] |
Lysosomal and lipase deficiency | |||||
Lysosomal acid lipase deficiency (Wolman disease, cholesteryl ester storage disease) | LIPA lysosomal acid lipase | Cholesteryl esters, triglycerides, and other lipids within lysosomes of most tissues | Hepatosplenomegaly, ascites, calcified adrenal glands, vomiting, diarrhea with steatorrhea, progressive psychomotor degradation, anemia, cachexia, low muscle tone, jaundice, vomiting, developmental delay, anemia, poor absorption of nutrients from food | Impairment of the lipophagic pathway | [121,122,123,124] |
Mucolipidosis | |||||
Mucolipidosis IV | MCOLN1 (TRPML1) mucolipin-1 | Sphingolipids, phospholipids, mucopolysaccharides and glycoproteins in cells of almost all tissues, including liver, spleen and in fibroblasts | Intellectual disability, psychomotor retardation, hypotonia, retinal degeneration, strabismus, photophobia, myopia, amblyopia or blindness, iron-deficiency anemia, achlorhydria with elevated blood gastrin levels | Impairment of autophagy and lipolysis; accumulation of lysosomes, autophagosomes and autophagy substrates | [125,126,127,128] |
Sialidosis (mucolipidosis I) | NEU1 neuraminidase 1 | Sialic acid–containing compounds (sialyloligosaccharides and sialolipids) in lysosomes in bodily tissues | Type I: progressive neurological impairment without bone or joint abnormalities; type II: mental retardation, severe hepatosplenomegaly, coarse facial features, dysostosis multiplex, seizures, myoclonus, ataxia, aminoaciduria, corneal opacity, macular cherry-red spot, skeletal abnormalities | Impairment of lipolysis and autophagy | [129,130,131] |
Neutral lipid storage disease | |||||
Neutral lipid storage disease with myopathy | PNPLA2 adipose triglyceride lipase (ATGL) | Triglycerides in muscle and other tissues | Myopathy, fatty liver, cardiomyopathy, pancreatitis, hypothyroidism, type 2 diabetes | Impairment of lipolysis | [132,133,134] |
Chanarin–Dorfman syndrome (neutral lipid storage disease type I, neutral lipid storage disease with ichthyosis) | ABHD5 abhydrolase domain containing 5 (activator of ATGL) | Triglycerides in organs and tissues, including skin, liver, muscles, intestine, eyes and ears | Ichthyosis, hepatomegaly, cataracts, ataxia, hearing loss, short stature, myopathy, nystagmus, mild intellectual disability | Impaired long-chain fatty acid oxidation; impaired BECN1-induced autophagic flux | [135,136,137] |
Xanthomatosis | |||||
Cerebrotendinous xanthomatosis (CTX) | CYP27A1 sterol 27-hydroxylase | Cholestanol and bile alcohols in the blood | Neonatal cholestasis, childhood-onset cataract, tendon and brain xanthomata, neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, seizures and neuropathy), liver dysfunction, intellectual impairment, neuropsychiatric symptoms (hallucinations, aggression and depression) | Induced autophagy | [138,139,140] |
Plant sterol storage disease | |||||
Sitosterolemia | ABCG5 or ABCG8 sterolin | Plant sterols, such as sitosterol, and LDL in the blood | Atherosclerosis, increased chance of a heart attack, stroke or sudden death, xanthomas, joint stiffness and pain, hemolytic anemia, macrothrombocytopenia | Accumulation of autophagic vacuoles | [141,142] |
Farber lipogranulomatosis | |||||
Farber disease (Farber lipogranulomatosis) | ASAH1 acid ceramidase | Lipids in cells and tissues throughout the body, particularly around the joints. | Lipogranulomas, swollen and painful joint deformity, subcutaneous nodules, hoarseness, difficulty breathing, hepatosplenomegaly, developmental delay, vomiting | Impairment of autophagic flux | [143] |
Fucosidosis | |||||
Fucosidosis | FUCA1 alpha-L-fucosidase | Fucose containing glyco-lipids and polysaccharides in the brain, liver, spleen, skin, heart, pancreas and kidneys | Intellectual disability, dementia, delayed development of motor skills, impaired growth, dysostosis multiplex, seizures, spasticity, angiokeratomas, coarse facial features, recurrent respiratory infections, visceromegaly | Induction of the autophagic cell death | [144] |
Lipid metabolism diseases | |||||
Familial hyperlipidemia | |||||
Hyperlipoproteinemia | |||||
Familial dysbetalipoproteinemia (hyperlipoproteinemia type III) | APOE apolipoprotein E | Chylomicrons and VLDL remnants in plasma | Palmar and tuberoeruptive xanthomas, coronary heart disease, peripheral vascular disease | Decreased lipolysis | [145,146,147,148] |
Familial hypercholesterolemia (hyperlipoproteinemia type IIa) | LDLR LDL receptor | LDL in plasma | Tendon xanthomas, coronary heart disease, increased chance of a heart attack, stroke or sudden death | Impairment of autophagic flux; altered autophagy flux by persistent mitophagy | [149,150,151] |
Familial defective apoB-100 (hyperlipoproteinemia type IIa) | APOB apolipoprotein B-100 | LDL in plasma | Tendon xanthomas, coronary heart disease, increased chance of a heart attack, stroke or sudden death | Impairment of autophagic flux; altered autophagy flux by persistent mitophagy | [151,152] |
Familial chylomicronemia syndrome | |||||
ApoA-V deficiency | APOA5 apolipoprotein A-V | Chylomicrons and VLDL in blood | Eruptive xanthomas, hepatosplenomegaly, pancreatitis | Impairment of lipolysis | [153,154] |
GPIHBP1 deficiency | GPIHBP1 glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 | Chylomicrons in plasma | Eruptive xanthomas, pancreatitis | Impairment of lipolysis | [155,156] |
Lipoprotein lipase deficiency (hyperlipoproteinemia type I) | LPL lipoprotein lipase | Chylomicrons in plasma | Eruptive xanthomas, abdominal pain, lipemia retinalis, hepatosplenomegaly, pancreatitis | Impairment of lipolysis | [157,158] |
Familial apolipoprotein C-II deficiency (hyperlipoproteinemia type I) | APOC2 apolipoprotein C-II (LPL cofactor) | Chylomicrons in plasma | Eruptive xanthomas, abdominal pain, lipemia retinalis, hepatosplenomegaly, pancreatitis | Impairment of lipolysis | [159,160,161] |
Familial hepatic lipase deficiency | LIPC hepatic lipase | VLDL remnants and IDLs in plasma | Pancreatitis, coronary heart disease, increased chance of a heart attack, stroke or sudden death | Impairment of lipolysis | [162] |
Familial hypercholesterolemia | |||||
Autosomal recessive hypercholesterolemia | LDLRAP1 (ARH) low-density lipoprotein receptor adaptor protein 1 | LDL in plasma | Tendon xanthomas, coronary heart disease, increased chance of a heart attack, stroke or sudden death | Induced autophagy | [73,163,164] |
Autosomal dominant hypercholesterolemia | PCSK9 proprotein convertase subtilisin/kexin type 9 | LDL in plasma | Tendon xanthomas, coronary heart disease, increased chance of a heart attack, stroke or sudden death | Increased autophagic flux | [73,165,166] |
Secondary Storage Lipid | Disease | Compartment | Cellular Disturbance | Reference |
---|---|---|---|---|
Phospholipids | ||||
Sphingomyelin | Sphingolipidoses: Niemann–Pick type C | Lysosomes | Altered membrane lipids trafficking | [170,171] |
Bis(monoacylglycero)phosphate (BMP) | Sphingolipidoses: Niemann–Pick type C, Fabry disease, Gaucher disease, GM1 gangliosidosis, GM2 gangliosidosis Mucopolysaccharidoses: Hurler syndrome, Hunter syndrome Neuronal ceroid lipofuscinoses: NCL 10 | Endosomes, lysosomes | Altered membrane lipids trafficking, lamellar bodies formation | [171,172] |
Glycosphingolipids | ||||
Gangliosides—GM1, GM2, GM3, GD1a, GD2, GD3 | Sphingolipidoses: Niemann–Pick type A, B and C, Gaucher disease, prosaposin deficiency Mucopolysaccharidoses: Hurler syndrome, Hunter syndrome, Sanfilippo syndrome, Maroteaux–Lamy syndrome, Sly syndrome Glycoproteinoses: Galactosialidosis, α-mannosidosis, sialidosis Mucolipidoses: mucolipidosis II/III, mucolipidosis IV Neuronal ceroid lipofuscinoses: NCL 3, NCL 6, NCL 10 | Late endosomes, lysosomes, cytoplasmic vesicles | Alteration of lysosomal pH, autophagy dysregulation, rupture of H+/Ca2+ homeostasis, altered vesicle trafficking, dysregulation of signaling pathways, accumulation of polyubiquitinated proteins, reduced capacity of immune cells to produce cytokines and antibodies, neurodegeneration (gliosis, demyelination of white matter, astrocyte and microglial activation) | [173,174,175,176,177,178,179,180,181] |
Cholesterol | ||||
Cholesterol | Sphingolipidoses: Niemann–Pick type A and B Mucopolysaccharidoses: Hurler syndrome, Hunter syndrome, Sanfilippo syndrome, Maroteaux–Lamy syndrome Glycoproteinoses: α-mannosidosis | Late endosomes, lysosomes, cytoplasmic vesicles | Impaired vesicle trafficking, abnormal sequestration of materials, foam cells in cerebral blood vessels and liver | [171,174,176,177,178] |
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Kloska, A.; Węsierska, M.; Malinowska, M.; Gabig-Cimińska, M.; Jakóbkiewicz-Banecka, J. Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases. Int. J. Mol. Sci. 2020, 21, 6113. https://doi.org/10.3390/ijms21176113
Kloska A, Węsierska M, Malinowska M, Gabig-Cimińska M, Jakóbkiewicz-Banecka J. Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases. International Journal of Molecular Sciences. 2020; 21(17):6113. https://doi.org/10.3390/ijms21176113
Chicago/Turabian StyleKloska, Anna, Magdalena Węsierska, Marcelina Malinowska, Magdalena Gabig-Cimińska, and Joanna Jakóbkiewicz-Banecka. 2020. "Lipophagy and Lipolysis Status in Lipid Storage and Lipid Metabolism Diseases" International Journal of Molecular Sciences 21, no. 17: 6113. https://doi.org/10.3390/ijms21176113