Perilipin-5

Perilipins are considered to have evolved from a common ancestral gene. This family began to split during the first and second vertebrate genome duplication,[9] giving birth to six types of PLIN genes, expressed throughout the animal kingdom. However, not all types are present in all animals. In fish, PLIN 1 to 6 can be found, whereas in mammals only PLIN1 to 5.[10]

Perilipin-5 possible evolution and its expressions in other species

PLIN5, as well as the other members of this protein family, is involved in lipid storage and also has energetic functions. Perilipin 5 coats the lipid droplet acting as a barrier to triglyceride, thus increasing its storage.[15] Under basal condition, PLIN5 decreases lipolysis to prevent energy waste. If energy is needed, perilipin facilitates lipid droplets with lipases and promotes enzymatic activity, regulating energy consumption.[16]

The mechanism by which OXPAT5 balances energy remain to be fully clarified. It interacts mainly with LDs, though recent data suggest that this protein also targets the nucleus. When needed, perilipin 5 is phosphorylated by protein kinase A, which allows it to access the nucleus and enter the complex SIRT1/PGC-1α, involved in fatty acid oxidation. PLIN5 removes SIRT1 inhibitor DBC1, therefore increasing its activity. As a consequence, PGC-1α boost activity levels activating certain types of genes that enhances mitochondrial function.[17]

PLIN5 is phosphorylated and it accesses the nucleus displacing DBC1 inhibitor

Higher levels of perilipin 5 are closely related to the association between lipid droplet and mitochondria. This is useful in case of starvation (energy shortage). When energy is needed and no glucose is available, the cell uses lipids to feed itself. In order to do that, lipid droplets move towards the mitochondria to transfer the stored fatty acids. The perilipin family opens the channel, giving way to lipids to access the mitochondria. On the other hand, this association may occur with the aim of protecting the mitochondria against toxic levels of fatty acids in the cytosol.[18]

PLIN5 is an enhancer of the erythrocytes count in blood, as well as hemoglobin concentration.[19]

Mammalian Plin's are not necessary for Lipid Droplet biogenesis, but as they are the primary regulators of lipolysis, they control cellular TAG/CE levels, long-chains whose functions is to provide enough metabolic precursors as polar lipids, which will then create Lipid Droplets.

Perilipin 5 overexpression causes LD enlargement, accumulation of triglycerides (TAG) and mitochondria dysfunction, causing severe health issues.

An increase in PLIN5 expression leads to the accumulation of triglyceride content and to the enlargement of LDs and a reduction in its number. This results in cardiac steatosis, an abnormal retention of lipids within a cell. Despite massive steatosis, overexpression of cardiac PLIN5 is compatible with normal heart function and lifespan.[21] Overexpression of PLIN5 also results in concentric hypertrophia on the left ventricle.[22]

Overexpression of PLIN5 causes a change in mitochondrial function as it leads to the "recruitment" of mitochondria to the LD and changes its morphology. Such LD-mitochondria assemblies typically move in unison due to their tight association. This mitochondrial phenotype was only observed in close proximity to LDs. [23][24]

PLIN5 plays an important role in regulating lipid accumulation and its breakdown in the liver. It appears that statins, a class of lipid-lowering medication, were effective in treating fatty liver diseases in non-alcoholic patients, as it decreased the hepatic expression of PLIN5, thus decreasing lipid accumulation.[25]

When LDs are lost due to a deficiency in PLIN5, FAs are not sequestered as TAG in LD and therefore larger amounts of FAs are oxidized in the mitochondria leading to an excess generation of reactive oxygen species (ROS). Medium and high concentrations of ROS can induce apoptosis and eventually cause necrosis through oxidative stress.[26] PLIN deficiency also reduces superoxide dismutase (SOD) activity. Furthermore, deficiency in PLIN5 initiates excessive phosforilation of PI3K/Akt which contributes to ischemia-reperfusion injury aggravation.

PLIN5-knockout diabetic mice might avoid excess accumulation of lipotoxic molecules such as DAG and ceramide, a common problem among diabetic patients. The built up of DAG and ceramide disrupts several signaling pathways, including PKC pathway. However, in humans, the association is not clear and the packaging of TAG into lipid droplets may be of critical importance in determining whether the accumulation of excess lipids exert a toxic effect on the myocardium.

It was found that a deficiency in Plin5 reduces mitochondrial oxidative capacity in mouses. Mitochondria from hearts suffering from a Plin5 deficiency had a membrana whose fatty acyl composition was altered, and its depolarization was compromised.[27]

It was also discovered in mice that, if a whole body deficiency of Plin5 was to happen, cardiac lipid droplet formation ability would be reduced, increasing fatty acid oxidations and promoting cardiac dysfunction. This, however, could be prevented by anti-oxidative therapy.

Deficiency in PLIN5 increases monocytes which are critical participants in the inflammation process. Because inflammation is essential to atherosclerosis, a deficiency in PLIN5 increases atherosclerosis risk.[28]