What is Perilipin-2 and Its Role in Fat Storage?

Perilipin-2, also known as adipophilin or PLIN2, is a protein that coats small fat-storing structures within cells. It is part of a larger family of five perilipin proteins (PLIN1-5) that regulate lipid metabolism. Unlike some of its counterparts found only in specific cells, Perilipin-2 is widespread in nearly all mammalian cell types, where it manages the storage and breakdown of fats. Its presence is a direct indicator of lipid accumulation within a cell.

The Function of Perilipin-2 in Cellular Fat Storage

Inside cells, excess fat is stored in organelles called lipid droplets. Perilipin-2 is one of the most abundant proteins on the surface of these droplets, where it forms a protective barrier. This coating acts as a gatekeeper, physically blocking enzymes called lipases from breaking down the stored lipids, a process known as lipolysis.

This function maintains a balance between storing fat and releasing it for energy. By stabilizing the lipid droplet, Perilipin-2 helps cells accumulate fat without it being immediately consumed. While it prevents uncontrolled breakdown, it is more permissive to fat release than other perilipins. This allows for a controlled turnover of fats, ensuring cells have access to energy when needed while preventing the toxic buildup of free fatty acids in the cytoplasm.

Perilipin-2’s Presence Across Body Tissues

The function of Perilipin-2 has different implications depending on the tissue, with a notable impact in metabolically active areas. In liver cells, or hepatocytes, high levels of Perilipin-2 are directly associated with the accumulation of lipid droplets. This process is linked to liver disease, as the protein helps sequester large amounts of fat within the liver.

In skeletal muscle, lipid droplets serve as a fuel source for physical activity, and Perilipin-2 helps manage these fat stores. Increased PLIN2 in muscle can lead to more lipid droplets, which can improve the muscle’s insulin sensitivity by safely partitioning fatty acids. In professional fat-storing cells, called adipocytes, Perilipin-2 is present but is secondary to Perilipin-1, the dominant protein on large lipid droplets in these specialized cells.

The protein also appears in immune cells called macrophages. When macrophages absorb excess lipids like cholesterol, they transform into “foam cells.” Perilipin-2 coats the lipid droplets inside these cells, facilitating cholesterol storage and contributing to the formation of these foam cells, a process linked to several diseases.

The Link Between Perilipin-2 and Disease

Disrupted Perilipin-2 regulation can contribute to several metabolic diseases. Its role in liver fat storage is a factor in non-alcoholic fatty liver disease (NAFLD). In NAFLD, elevated Perilipin-2 in hepatocytes promotes fat accumulation, leading to steatosis, the disease’s initial stage. Studies in mice show that deleting the PLIN2 gene can protect against diet-induced steatosis and liver inflammation.

The protein is also connected to obesity and insulin resistance. By facilitating fat storage in tissues not designed for it, like muscle and liver (a condition known as ectopic fat storage), Perilipin-2 contributes to cellular stress that can cause insulin resistance. High levels of the protein are associated with obesity, and its absence in animal models prevents high-fat diet-induced obesity and related inflammation.

Its function in macrophages directly links it to atherosclerosis. The formation of foam cells, supported by Perilipin-2’s role in lipid storage, is an early step in the development of arterial plaques. These plaques can narrow arteries and increase the risk of cardiovascular events. Research suggests reducing Perilipin-2 in macrophages could enhance cholesterol removal from these cells, potentially slowing plaque development.

How Diet and Lifestyle Affect Perilipin-2

The amount of Perilipin-2 in cells is influenced by diet and physical activity. A high-fat diet increases Perilipin-2 expression by activating transcription factors like PPARγ, which switches on the gene that produces the protein. This enhances the cell’s capacity to store excess dietary fat.

Fasting or caloric restriction can also alter Perilipin-2 levels. During fasting, the body must access its stored fat reserves. Some studies indicate that fasting leads to the degradation of Perilipin-2, allowing lipases greater access to lipid droplets to release fatty acids for energy.

Exercise also influences the metabolism of lipids within muscle, a process involving the perilipin protein family. During physical activity, muscle cells use their internal lipid droplets for fuel. The breakdown of these fats is managed by proteins on the droplet surface, including Perilipin-2. Regular exercise can influence the entire lipid management system within muscle cells, affecting how fats are stored and utilized for energy.