Fat Cell Exosomes Demonstrated to Impair the Ability of Macrophages to Remove Cholesterol from Blood Vessel Walls

Carrying excess visceral fat tissue, the fat packed around organs in the abdomen, accelerates all of the common conditions of aging. This is most likely largely mediated by chronic inflammation, the overactivation of the immune system that fat tissue produces. Numerous mechanisms contribute to this inflammation: fat tissue generates an outsized number of lingering senescent cells that secrete inflammatory signals; dying fat cells produce DNA debris that triggers an immune response; fat cells burdened by a lot of lipids generate similar signals to those released by infected cells; and so forth.

Chronic inflammation is particularly important in the progression of atherosclerosis. Cholesterols in the bloodstream find their way into blood vessel walls, and must be removed by the innate immune cells known as macrophages, which hand off the cholesterol to high-density lipoprotein (HDL) particles for it to be carried back to the liver for excretion. With age, rising levels of inflammation and oxidative stress generate ever more oxidized cholesterols, and these damaged molecules, particularly 7-ketocholesterol, cause macrophages to become dysfunctional. Further, chronic inflammation causes macrophages to act inappropriately, becoming inflammatory themselves rather than usefully engaging in removing cholesterol from blood vessel tissue. The result is fatty lesions, formed of cholesterols and the debris of dead macrophages, overwhelmed trying to help. The more inflammatory signaling there is, the more macrophages are called in to their doom.

In the research results I'll point out today, scientists have found another way in which fat tissue can degrade the ability of macrophages to remove cholesterol from blood vessel walls, operating independently of inflammatory mechanisms. Exosomes, a form of membrane-bound extracellular vesicle packed with signal molecules, are released by fat cells and, when taken up by macrophages, impair the ability of those macrophages to carry out the action of passing a cholesterol molecule to an HDL particle. While the study was carried out in young people, I would expect the mechanism to operate in older individuals as well. There are already countless very good reasons to avoid becoming fat: it is arguably the case that being overweight literally accelerates the aging process. Nonetheless, here is another one.

MicroRNAs from human fat cells can impair macrophage ability to eliminate cholesterol

In atherosclerosis, blood vessels that carry oxygen-rich blood throughout the body become inflamed, and macrophages settle in the vessel wall and become overloaded with cholesterol. A plaque forms that restricts blood flow. But it remains a mystery how fat cells residing in one place in the body can trigger mayhem in cells and tissues located far away. Extracellular vesicles (EVs) seemed likely troublemakers since they enable intercellular communication. "We found that seven specific small sequences of RNA (microRNA) carried within the extracellular vesicles from human fat tissue impaired the ability of white blood cells called macrophages to eliminate cholesterol. Fat isn't just tissue. It can be thought of as a metabolic organ capable of communicating with types of cells that predispose someone to develop atherosclerotic cardiovascular disease, the leading cause of death around the world."

Because heart disease can have its roots in adolescence, the researchers enrolled 93 kids aged 12 to 19 with a range of body mass indices (BMIs), including the "lean" group, 15 youth whose BMI was lower than 22 and the "obese" group, 78 youths whose BMI was in the 99th percentile for their age. Their median age was 17. Seventy-one were young women. The researchers collected visceral adipose tissue during abdominal surgeries. "We were surprised to find that EVs could hobble the macrophage cholesterol outflow system in adolescents of any weight. It's still an open question whether young people who are healthy can tolerate obesity - or whether there are specific differences in fat tissue composition that up kids' risk for heart disease."

Cholesterol efflux alterations in adolescent obesity: role of adipose-derived extracellular vesical microRNAs

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide. Although primarily a disease of adults, youth with obesity show evidence of subclinical ASCVD which places them at increased risk as adults for coronary heart disease and stroke. The mechanisms by which obesity confers cardiovascular risk are not fully understood, but inflammation within visceral adipose tissue (VAT) is thought to be contributory. Further, the impact of excess adipose tissue on distal sites such as arterial wall monocytes/macrophages, direct participants in ASCVD, are also thought to contribute to disease pathogenesis.

In this study we show, for the first time, significant alterations in cholesterol efflux capacity in adolescents throughout the range of BMI, a relationship between six circulating adipocyte-derived EVs microRNAs targeting ABCA1 and cholesterol efflux capacity, and in vitro alterations of cholesterol efflux in macrophages exposed to visceral adipose tissue adipocyte-derived EVs acquired from human subjects. These results suggest that adipocyte-derived EVs, and their microRNA content, may play a critical role in the early pathological development of ASCVD.


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