Key enzyme controls both weight gain and cholesterol levels in animal models

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"... Nitric oxide is a gas molecule with pleiotropic actions in the body. These effects of nitric oxide are carried out through its binding to proteins. Too much or too little nitric oxide binding (to key proteins) causes disease.

In a study ... a research team ... discovered a novel enzyme (SCoR2) that removes nitric oxide from proteins controlling fat build up. Removal of nitric oxide turned on fat synthesis, establishing that SCoR2 is needed to make fat.

The team then inhibited SCoR2 genetically and by developing a drug. They found that blocking this nitric oxide-removing enzyme prevented weight gain and liver injury in mouse models. The same drug also lowered bad cholesterol.

"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," ..."

"... 

• Cleveland research team has discovered a new enzyme that is required to make fat.
• Blocking the enzyme prevented weight gain and lowered cholesterol.
• A three-in-one drug is being developed to treat obesity, fatty liver disease, and cardiovascular disease.

..."

From the editor's summary and abstract:

"Editor’s summary

Hypertrophy of white adipose tissue due to triglyceride storage and steatosis in the liver due to excessive de novo lipogenesis have detrimental metabolic effects. Venetos et al. found that these processes were stimulated by the enzymatic removal of S-nitrosyl (SNO) groups from distinct protein targets in white adipose tissue and liver by the denitrosylase SCoR2.
Mice deficient in SCoR2 or given a SCoR2 inhibitor were metabolically protected from obesogenic diets because of increased fatty acid oxidation in the liver and reduced adipose tissue expansion.
Moreover, SCoR2 mRNA or protein abundance correlated with obesity, adipocyte surface area, or steatotic liver disease in patients. Thus, because SCoR2 activity skews global lipid metabolism toward storage and synthesis, this denitrosylase could be targeted to treat both obesity and hepatic steatosis. ...

Abstract

Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)–dependent acetylation.

Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health.
In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction–associated steatotic liver disease (MASLD).
Loss of SCoR2 in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage.
In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation.
In humans, an obesity-linked polymorphism was associated with increased SCoR2 mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD.
These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD."

Key enzyme controls both weight gain and cholesterol levels in animal models

Cleveland Researchers Discover Enzyme That Controls Both Weight Gain and Cholesterol Levels in Animal Models (original news release)

The protein denitrosylase SCoR2 regulates lipogenesis and fat storage (no public access)