PLIN1: Storing and Breaking Down Fat

Key takeaways:
~ PLIN1 is a protein that regulates lipolysis – the breakdown of fat cells for energy.
~ Genetic variants in PLIN1 can affect how easily someone loses weight on different diets.

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What is PLIN1?

The PLIN1 gene (perilipin 1) codes for the protein that is a structural component of the lipid droplets in fat cells (adipocytes). This coating protects the lipid droplets from the enzymes that break down fats for use as energy in the body.

While most know that fat cells store lipids so that they can later be used for energy, the way that lipid droplets are formed and stored is way more complex than I had realized.

Studies show that the lipid droplet in fat cells and other cells is covered by a thin layer of phospholipids and cholesterol, with various proteins embedded into that thin layer. The most abundant proteins on the surface of lipid droplets are perilipins. Five different perilipin proteins are expressed in different tissues of the body.[ref]

We’re going to focus in here on perilipin 1 (PLIN1), which is found in adipose tissue and is involved in how the body stores and uses fat for energy.

When cells in the body need more energy (e.g. fasting, exercising), lipids from your adipocytes (fat cells) are released through a process called lipolysis. Lipases are the enzymes that cause lipolysis. I picture it like a drop of dishwashing detergent breaking up fat when washing a dirty pan.

Lipase enzymes are activated and moved to the surface of lipid droplets when cells need energy. Perilipin 1, on the surface of lipid droplets in adipocytes, is a gatekeeper that keeps lipolysis in check. It does this by binding to ABHD5, which prevents ABHD5 from interacting with and activating the lipase enzymes. When energy is needed, PLIN1 becomes phosphorylated via PKA and releases ABHD5, which in turn binds with the lipases to cause lipid release from the droplet.[ref]

There’s a little more to this story. Newly identified in a 2024 study is another protein, APOL6, that interacts with PLIN1. In the fasted state, APOL6 levels are low, but in the fed state, APOL6 levels increase significantly and lipolysis is inhibited. APOL6 interacts with PLIN1 to prevent the signal from the lipase enzymes (HSL).[ref]

Yes, that was a lot of technical detail to say that PLIN1 on the outside of lipid droplets keeps them from being broken down.

PLIN1 and metabolic health:

Increased levels of PLIN1 are associated with obesity because the fat cells can’t be broken down as easily. On the other hand, decreased PLIN1 causes leanness. Mice bred to be deficient in perilipin eat more than wild-type mice but gain half the fat weight.[ref] However, perilipin 1 is important to the regulation of metabolism, and completely knocking out the PLIN1  gene in mice causes inflammation and disordered fat regulation.[ref]

The details: A study laid out how exactly perilipin works to control lipolysis (breakdown of fats for energy).  Phosphorylation of perilipin changes the coating of the fat molecules and allows enzymes access to break down the fat for energy.  The pathway goes as follows:  “Catecholamines bind β-adrenergic receptors, which signal through a heterotrimeric G-protein to activate adenyl cyclase, thereby elevating cAMP levels and activating PKA. This step takes place in seconds or faster. PKA phosphorylates both perilipin A and HSL. Maximal phosphorylation of perilipin A takes place in less than 2 minutes,” [ref]

Lipolysis is regulated by the levels of several enzymes – adipose triglyceride lipase (PNPLA2), hormone-sensitive lipase (HSL), and monoglyceride lipase. When you have fasted for a while, hormones initiate the signaling cascade to increase lipolysis. Phosphorylation then activates several cellular processes to mobilize the lipids.[ref]

Genetics and PLIN1:

Multiple studies have shown that people with PLIN1 variants that cause decreased function are less likely to have metabolic health problems.

A 2022 study looked at over 400,000 people in the UK and found that having uncommon mutations that decreased PLIN1 function was associated with:[ref]

• lower triglycerides
• reduces waist-to-hip ratio
• reduced blood pressure
• higher HDL cholesterol

More common genetic variants are linked to an increased risk of insulin resistance when eating more saturated fat.[ref]

Role in Lipodystrophy and Metabolic Disorders:
Rare mutations in PLIN1 can cause familial partial lipodystrophy type 4 (FPLD4), which is a really rare genetic disorder characterized by abnormal fat distribution, insulin resistance, PCOS, and dyslipidemia. In this condition, fat is lost from some areas of the body while accumulating in others, often leading to metabolic complications.[ref][ref]

Overall, a picture emerges of needing PLIN1  at the right level to prevent insulin resistance and obesity. Too much or too little PLIN1 are associated with metabolic problems.

Lifehacks:

Your PLIN1 genetic variants may play a role in insulin resistance, PCOS due (to insulin resistance), and the ability to lose weight easily on a diet. Keep in mind, though, that there are a number of genetic variants related to diet and weight that all should be taken into account when coming up with an individual weight loss plan. Members can view their overview of weight-related genes here.

Dietary interactions:

For people with the C allele of rs2289487, increasing protein on a lower-calorie diet may be more effective for weight loss.

For people with the T allele in rs894160, a high saturated fat intake may increase the risk of insulin resistance. The study on this found that higher carb-to-fat intake may mitigate the increased risk. Combined with the research on complex carbs, a picture emerges that eating complex carbohydrates (not processed carbs) while not going overboard on saturated fat would be the best bet for mitigating the risk of insulin resistance. Complex carbohydrates are found in vegetables, whole grains, and beans.[ref][ref][ref]

Stimulating more lipolysis:

PKA – protein kinase A – phosphorylates PLIN1. In adipocytes, this is stimulated by epinephrine (adrenaline) through beta-adrenergic receptors or glucagon via the glucagon receptor. One way to stimulate epinephrine, PKA, PLIN1, and lipolysis is through exercise.

Supplements that suppress PLIN1:

A studies in adipose cell samples and mice showed that the following supplements significantly suppressed PLIN1 expression and decreased weight gain:

• berberine
• luteolin
• fisetin
• quercetin
• EGCG
• hesperidin
• curcumin

Resveratrol and fucoidan had less of an effect but still decreased PLIN1 expression a bit.[ref]

Related articles and topics:

Fatty Liver: Genes that increase the risk of NAFLD

Insulin Resistance and Genetics: Finding the Root Cause