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A tiny chemical signal inside our cells may hold a big key to reversing obesity and fatty liver disease. Researchers in Cleveland have isolated an enzyme that flips the metabolic switch on fat production — and in mice, turning that enzyme off prevented weight gain and improved cholesterol.
The molecule at the center of this story is nitric oxide, a short-lived gas that doubles as a signaling molecule in the body. Nitric oxide modifies proteins by attaching to specific amino acids, a process scientists call S-nitrosylation. That chemical tag can dampen or alter a protein’s activity. When this tagging system gets thrown out of balance, cellular metabolism can unravel, contributing to conditions such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD).
What the Cleveland team found is a previously unrecognized enzyme named SCoR2. Unlike enzymes that add chemical tags, SCoR2 removes nitric oxide from proteins — a denitrosylase, in effect. By stripping nitric oxide off proteins involved in fat and cholesterol synthesis, SCoR2 flips them into an active state. In plain language: SCoR2 helps switch on the machinery that builds fat.
How blocking SCoR2 changes metabolism
The investigators used both genetic deletion and a newly designed small molecule to block SCoR2 in mice. The metabolic outcomes were striking. Animals protected from SCoR2 activity resisted diet-driven weight gain. Their livers showed less fat accumulation and reduced markers of liver injury. At the same time, levels of atherogenic cholesterol fell.
Those effects arise from two related mechanisms. In the liver, nitric oxide ordinarily suppresses enzymes that manufacture fat and cholesterol; SCoR2 removes that suppression by denitrosylating key proteins, allowing lipid production to proceed. In adipose tissue, nitric oxide restrains the genetic program that produces the enzymes needed for fat synthesis; SCoR2 again counteracts that restraint. Block SCoR2 and those brakes stay engaged — less fat is made, and circulation holds less harmful cholesterol.
Lead author Jonathan Stamler, a cardiometabolic researcher affiliated with University Hospitals and Case Western Reserve University, described the findings as the first demonstration of a druggable enzyme that both prevents weight gain and lowers harmful cholesterol levels. "We have a new class of drug that prevents weight gain and lowers cholesterol — a potential therapy for obesity and cardiovascular disease, with additional hepatic benefits," he said.
These experiments used controlled mouse models, so how this translates to people remains an open and urgent question. The team plans to move the compound toward clinical trials within roughly 18 months, aiming to test safety and efficacy in humans. If the drug behaves similarly in people, it could offer a dual-action approach: tackling excess weight while protecting the liver and reducing cardiovascular risk.
The discovery also reframes how scientists think about metabolic control. Rather than a one-way cascade of hormones and nutrients, fat synthesis appears to be governed by a dynamic chemical tug-of-war: nitric oxide adds inhibitory marks, SCoR2 removes them, and the outcome determines whether cells store energy as fat or not. Targeting the enzymes that resolve those marks gives researchers a new lever to adjust metabolism.
Still, several caveats remain. Long-term effects of altering nitric oxide signaling are not fully known. Nitric oxide participates in blood pressure regulation, immune responses, and neuronal signaling. Any therapy that shifts its activity will need careful safety testing to avoid unintended consequences.
For now, the work offers a rare combination of mechanistic insight and therapeutic promise. It points to a tractable biochemical switch — SCoR2 — whose inhibition dampens fat creation and improves cholesterol profiles in preclinical models. Whether that switch will unlock new treatments for obesity and MASLD in people is the next chapter, one that clinical trials will begin to write.
Source: scitechdaily
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