| PLIN1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | PLIN1 , FPLD4, PERI, PLIN, perilipin 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 170290 MGI: 1890505 HomoloGene: 2001 GeneCards: PLIN1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. [5] The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue. [6]
Perilipin is part of a gene family with six currently-known members. In vertebrates, closely related genes include adipophilin (also known as adipose differentiation-related protein or Perilipin 2), TIP47 (Perilipin 3), Perilipin 4 and Perilipin 5 (also called MLDP, LSDP5, or OXPAT). Insects express related proteins, LSD1 and LSD2, in fat bodies. [7] The yeast Saccharomyces cerevisiae expresses PLN1 (formerly PET10), that stabilizes lipid droplets and aids in their assembly. [8]
The perilipins are considered to have their origins in a common ancestral gene which, during the first and second vertebrate genome duplication, gave rise to six types of PLIN genes. [9]
Human perilipin-1 is composed by 522 amino acids, which add up to a molecular mass of 55.990 kDa. It presents an estimated number of 15 phosphorylation sites (residues 81, 85, 126, 130, 132, 137, 174, 299, 301, 382, 384, 408, 436, 497, 499 and 522) [11] from which 3 -those in bold- have been suggested to be relevant for stimulated-lipolysis through PKA phosphorylation - they correspond respectively to PKA Phosphorylation sites 1, 5 and 6. [12] A compositional bias of Glutamic acid can be found between residues 307 and 316. [13] Its secondary structure has been suggested to be conformed exclusively by partially hydrophobic α-helixes, [10] as well as the respective coils and bends.
Whereas perilipin-1 is coded by a single gene, alternative mRNA splicing processes can lead to three protein isoforms (Perilipin A, B and C). Both Perilipin A and B present common N-terminal regions, differing in the C-terminal ones. [14] Concretely, beginning from the N-terminal of Perilipin-1, a PAT domain—characteristic of its protein family—can be found, followed by an also characteristic repeated sequence of 13 residues which form amphipathic helixes with an active role in linking membranes [15] and a 4-helix bundle before the C-terminal carbon. [16] In Perilipin A, lipophile nature is conferred by the slightly hydrophobic amino acids concentrated in the central 25% of the sequence, region that anchors the protein to the core of the lipid droplet. [17]
| Perilipin | |||||||||||
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| Identifiers | |||||||||||
| Symbol | Perilipin | ||||||||||
| Pfam | PF03036 | ||||||||||
| InterPro | IPR004279 | ||||||||||
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Unlike its human ortholog, murine perilipin is composed of 517 amino acids in the primary structure of which several regions can be identified. Three moderately hydrophobic sequences (H1, H2, H3) of 18 rem (243-260 aa), 23 rem (320-332 aa) and 16 rem (349-364 aa) can be identified in the centre of the protein, as well as an acidic region of 28 residues where both glutamic and aspartic acids add up to 19 of them. Five sequences 18 residues long that could form amphipathic β-pleated sheets—according to a prediction made through LOCATE program—are found between aa 111 and 182.[ original research? ] Serines occupying positions 81, 222, 276, 433, 492 and 517 act as phosphorylation sites -numbered from 1 to 6- for PKA, [18] as well as several other threonines and serines which add up to 27 phosphorylation sites. [19]
Perilipin is a protein that coats lipid droplets (LDs) in adipocytes, [20] the fat-storing cells in adipose tissue. In fact, PLIN1 is greatly expressed in white adipocytes. [21]
It controls adipocyte lipid metabolism. [22] It handles essential functions in the regulation of basal and hormonally stimulated lipolysis [23] and also rises the formation of large LDs which implies an increase in the synthesis of triglycerides. [21]
In humans, Perilipin A is the most abundant protein associated with the adipocyte LDs [7] and lower PLIN1 expression is related with higher rates of lipolysis. [24]
Under basal conditions, Perilipin acts as a protective coating of LDs from the body's natural lipases, such as hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), [25] [24] which break triglycerides into glycerol and free fatty acids for use in lipid metabolism. [6]
In times of energy deficit, Perilipin is hyperphosphorylated by PKA following β-adrenergic receptor activation. [6] Phosphorylated perilipin changes conformation, exposing the stored lipids to hormone-sensitive lipase-mediated lipolysis.
Specifically, in the basal state Perilipin A allows a low level of basal lipolysis [26] by reducing the access of cytosolic lipases to stored triacylglycerol in LDs. [23] It is found at their surface in a complex with CGI-58, the co-activator of ATGL. ATGL might also be in this complex but it is quiescent. [27]
Under lipolytically stimulated conditions, PKA is activated and phosphorylates up to 6 Serine residues on Perilipin A (Ser81, 222, 276, 433, 492, and 517) and 2 on HSL (Ser659, and 660). [27] Although PKA also phosphorylates HSL, which can increase its activity, the more than 50-fold increase in fat mobilization (triggered by epinephrine) is primarily due to Perilipin phosphorylation[ citation needed ].
Then, Phosphorylated HSL translocates to the LD surface and associates with Perilipin A and Adipocyte fatty acid-binding protein (AFABP). [27] Consequently, HSL gains access to triacylglycerol (TAG) and diacylglycerol (DAG), substrates in LDs. Also, CGI-58 separates from the LD outer layer which leads to a redistribution of ATGL. [23] In particular, ATGL interacts with Perilipin A through phosphorylated Ser517. [27]
As a result, PKA phosphorylation implies an enriched colocation of HLS and ATGL which facilitates maximal lipolysis by the two lipases. [23]
Perilipin is an important regulator of lipid storage. [6] Both an overexpression or deficiency of the protein, caused by a mutation, lead to severe health issues.
Perilipin expression is elevated in obese animals and humans. Polymorphisms in the human perilipin (PLIN) gene have been associated with variance in body-weight regulation and may be a genetic influence on obesity risk in humans. [28]
This protein can be modified by O-linked acetylglucosamine (O-GlNac) moieties and the enzyme that intervenes is O-GlcNAc transferase (OGT). An abundance of OGT obstructs lipolysis and benefits diet-induced obesity and whole-body insulin resistance. Studies also propose that an overexpression of adipose O-GlcNAc signaling is a molecular expression of obesity and diabetes in humans. [29]
Perilipin-null mice eat more food than wild-type mice, but gain 1/3 less fat than wild-type mice on the same diet; perilipin-null mice are thinner, with more lean muscle mass. [30] Perilipin-null mice also exhibit enhanced leptin production and a greater tendency to develop insulin resistance than wild-type mice. Even though perilipin-null mice present less fat mass and a higher insulin resistance, they do not show signs of a whole lipodystrophic phenotype. [31]
In humans, studies suggest that a deficiency of PLIN1 causes lipodystrophic syndromes, [32] which disables the optimal accumulation of triglycerides in adipocytes that derives in an abnormal deposition of lipids in tissues such as skeletal muscle and liver. The storage of lipids in the liver leads to insulin resistance and hypertriglyceridemia. Affected patients are characterized by a subcutaneous fat with smaller than normal adipocytes, macrophage infiltration and fibrosis.
These findings affirm a new primary form of inherited lipodystrophy and emphasize on the severe metabolic consequences of a defect in the formation of lipid droplets in adipose tissue.
In particular, variants 13041A>G and 14995A>T have been associated with increased risk of obesity in women and 11482G>A has been associated with decreased perilipin expression and increased lipolysis in women. [33] [34]
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.
Adipose tissue (also known as body fat, or simply fat) is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction(SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and cytokines (especially TNFα). In obesity, adipose tissue is also implicated in the chronic release of pro-inflammatory markers known as adipokines, which are responsible for the development of metabolic syndrome, a constellation of diseases, including type 2 diabetes, cardiovascular disease and atherosclerosis. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue – more specifically brown adipose tissue – was first identified by the Swiss naturalist Conrad Gessner in 1551.
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.
Starvation response in animals is a set of adaptive biochemical and physiological changes, triggered by lack of food or extreme weight loss, in which the body seeks to conserve energy by reducing the amount of food energy it consumes.
Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene, and catalyzes the following reaction:
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.
Mannose-6-phosphate receptor binding protein 1 (M6PRBP1) is a protein which in humans is encoded by the M6PRBP1 gene. Its gene product, as well as the gene itself, is commonly known as TIP47.
Adipose differentiation-related protein, also known as perilipin 2, ADRP or adipophilin, is a protein which belongs to the perilipin (PAT) family of cytoplasmic lipid droplet (CLD)–binding proteins. In humans it is encoded by the ADFP gene. This protein surrounds the lipid droplet along with phospholipids and is involved in assisting the storage of neutral lipids within the lipid droplets.
Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.
1-acylglycerol-3-phosphate O-acyltransferase ABHD5, also known as comparative gene identification-58 (CGI-58), is an enzyme that in humans is encoded by the ABHD5 gene.
Cell death activator CIDE-A is a protein that in humans is encoded by the CIDEA gene. Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids.
Fibroblast growth factor 21 is a liver-secreted peptide hormone that in humans is encoded by the FGF21 gene. Together with FGF19 and FGF23, this protein is a member of the endocrine subgroup within the fibroblast growth factor (FGF) family. FGF21 is a potent, extracellularly acting metabolic regulator, whose action was discovered through in vitro phenotypic screening and diet manipulation studies in rodents., unlike canonical growth-stimulating FGFs known to stimulate mitosis, differentiation and angiogenesis in their target tissues, FGF21 exerts its action by activating FGF21 receptors located in the cell membrane of target cells. Each FGF21 receptor is composed of a transmembrane FGF receptor protein, and its complexing co-receptor β-Klotho. Loss of β-Klotho abolishes all effects of FGF21 in vitro and in vivo. In addition to its action as a hormone, FGF21 may be able to act in an autocrine fashion, or possibly also in a paracrine manner in the pancreas.
Neutral lipid storage disease is a congenital autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. It commonly occurs as one of two subtypes, cardiomyopathic neutral lipid storage disease (NLSD-M), or ichthyotic neutral lipid storage disease (NLSD-I) which is also known as Chanarin–Dorfman syndrome), which are characterized primarily by myopathy and ichthyosis, respectively. Normally, the ichthyosis that is present is typically non-bullous congenital ichthyosiform erythroderma which appears as white scaling.
Lipid droplets, also referred to as lipid bodies, oil bodies or adiposomes, are lipid-rich cellular organelles that regulate the storage and hydrolysis of neutral lipids and are found largely in the adipose tissue. They also serve as a reservoir for cholesterol and acyl-glycerols for membrane formation and maintenance. Lipid droplets are found in all eukaryotic organisms and store a large portion of lipids in mammalian adipocytes. Initially, these lipid droplets were considered to merely serve as fat depots, but since the discovery in the 1990s of proteins in the lipid droplet coat that regulate lipid droplet dynamics and lipid metabolism, lipid droplets are seen as highly dynamic organelles that play a very important role in the regulation of intracellular lipid storage and lipid metabolism. The role of lipid droplets outside of lipid and cholesterol storage has recently begun to be elucidated and includes a close association to inflammatory responses through the synthesis and metabolism of eicosanoids and to metabolic disorders such as obesity, cancer, and atherosclerosis. In non-adipocytes, lipid droplets are known to play a role in protection from lipotoxicity by storage of fatty acids in the form of neutral triacylglycerol, which consists of three fatty acids bound to glycerol. Alternatively, fatty acids can be converted to lipid intermediates like diacylglycerol (DAG), ceramides and fatty acyl-CoAs. These lipid intermediates can impair insulin signaling, which is referred to as lipid-induced insulin resistance and lipotoxicity. Lipid droplets also serve as platforms for protein binding and degradation. Finally, lipid droplets are known to be exploited by pathogens such as the hepatitis C virus, the dengue virus and Chlamydia trachomatis among others.
Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes. Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction. It was discovered as WY-14,643 in 1974.
Adipose tissue macrophages comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese, leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity.
Fat storage-inducing transmembrane protein 2 is a protein that in humans is encoded by the FITM2 gene. It plays a role in fat storage. Its location is 20q13.12 and it contains 2 exons. It is also a member of the FIT protein family that has been conserved throughout evolution. Conserved from Saccharomyces cerevisiae to humans is the capability to take fat and store it as cytoplasmic triglyceride droplets. While FIT proteins facilitate the segregation of triglycerides (TGs) into cytosolic lipid droplets, they are not involved in triglyceride biosynthesis. In mammals, both FIT2 and FIT1 from the same family are present, embedded in the wall of the endoplasmic reticulum (ER) where they regulate lipid droplet formation in the cytosol. In S. cerevisiae, it also plays a role in the metabolism of phospholipids. These TGs are in the cytoplasm, encapsulated by a phospholipid monolayer in configurations or organelles that have been given many different names including lipid particles, oil bodies, adiposomes, eicosasomes, and most prevalent in scientific research – lipid droplets.
Perilipin 4, also known as S3-12, is a protein that in humans is encoded by the PLIN4 gene on chromosome 19. It is highly expressed in white adipose tissue, with lower expression in heart, skeletal muscle, and brown adipose tissue. PLIN4 coats lipid droplets in adipocytes to protect them from lipases. The PLIN4 gene may be associated with insulin resistance and obesity risk.
Perilipin 5, also known as Oxpatperilipin 5 or PLIN5, is a protein that belongs to perilipin family. This protein group has been shown to be responsible for lipid droplet's biogenesis, structure and degradation. In particular, Perilipin 5 is a lipid droplet-associated protein whose function is to keep the balance between lipolysis and lipogenesis, as well as maintaining lipid droplet homeostasis. For example, in oxidative tissues, muscular tissues and cardiac tissues, PLIN5 promotes association between lipid droplets and mitochondria.
Hypoxia inducible lipid droplet-associated is a protein that in humans is encoded by the HILPDA gene.
