Elevated Circulating Fatty Acid Synthase Is a Diagnostic Biomarker for Peripheral Artery Disease

Elevated levels of a soluble form of the enzyme fatty acid synthase (sFSA) in the blood have been linked to development of the severe vascular disorder peripheral artery disease (PAD).

Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two identical multifunctional polypeptides, in which substrates are handed from one functional domain to the next. The main function of FSA is to catalyze the synthesis of palmitate (C16:0, a long-chain saturated fatty acid) from acetyl-CoA and malonyl-CoA, in the presence of NADPH.

In 2015, about 155 million people had PAD worldwide, and it becomes more common with age. In the developed world, PAD affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the United States PAD impacts some 12 million people. Among them at least 10% will progress to develop chronic limb-threatening ischemia (CLTI), a condition characterized by severe lower extremity arterial insufficiency, rest pain, non-healing wounds/ulcers, and gangrene.

There are currently no serum-based evaluations that can corroborate the severity of PAD. Therefore, in order to improve prognosis, the Global Vascular Guidelines recently highlighted the need for early diagnosis and aggressive medical management of patients. In this regard, investigators at Washington University School of Medicine (St. Louis, MO, USA) assessed the prevalence of elevated serum fatty acid synthase (cFAS) in patients with CLTI and evaluated the accuracy of its use in detecting this condition. This approach was based on prior studies showing that serum circulating FAS was elevated in patients with atherosclerotic carotid artery stenosis, and FAS content in carotid plaque was higher in maximally diseased segments.

For the current study, the investigators obtained and analyzed blood samples from 87 patients before they underwent vascular surgery to treat CLTI. Results revealed that elevated cFAS content, type II diabetes, and smoking were independently associated with CLTI and could detect the presence of CLTI with 83% accuracy. Levels cFAS in the blood were associated with the FAS content of plaque sampled from the femoral artery, the main vessel supplying blood to the legs. In addition, cFAS was found to circulate through the bloodstream while bound to the cholesterol transporter, low-density lipoprotein (LDL).

“These patients are at risk of losing their legs, which is devastating to quality of life,” said senior author Dr. Mohamed A. Zayed, associate professor of surgery and radiology at Washington University School of Medicine. “They lose their capacity to walk, and about half of them die within the next two years. We need to identify these patients sooner, so we can help treat them aggressively much earlier in the disease course. Our data suggest that levels of cFAS in the blood could be an accurate predictor for which patients are at high risk of the severe forms of this condition.”

“Oftentimes, I will see patients in my practice who have high LDL but are otherwise healthy individuals - they do not have evidence of disease in their arteries,” said Dr. Zayed. “Our guidelines tell us to be aggressive in treating these patients. But my suspicion is the problem is not just LDL. Rather, the problem is enzymes that are attached to LDL that are conferring the cardiovascular disease that we see, particularly in the peripheral arteries, as well as the coronary arteries that deliver blood to the heart and the carotid arteries that deliver blood to the brain.”

The study was published in the September 29, 2021, online edition of the journal Scientific Reports.

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Washington University School of Medicine