Scientists Identify Target for Obesity and Atherosclerosis

Scientists claim that an enzyme already implicated in the control of tumorigenesis through p53 activation may also directly act to control obesity and atherosclerosis. Wip1 phosphatase is a known negative regulator of ataxia telangiectasia mutated (Atm)-dependent signaling, and knocking out the Wip1 gene, which is amplified in a range of primary human cancers, has been shown to result in tumor resistance in a number of cancer-prone mouse models. Dmitry V. Bulavin, Ph.D., at the Institute of Molecular and Cell Biology and the Singapore Bioimaging Consortium (SBIC) have now found that Wip1 deficiency also makes mice resistant to diet-induced obesity and prevents the development of atherosclerosis in ApoE-knockout animals.

Their findings, reported in Cell Metabolism, indicate that Wip1’s role in controlling obesity and atherosclerosis is dependent on an Atm-mTOR signaling pathway that doesn’t involve p53. Instead, knocking out Wip1 prevents the accumulation of lipid droplets in macrophages and their conversion into foam cells through increased autophagy. Dr Bulavin, et al’s published paper is titled “Wip1-Dependent Regulation of Autophagy, Obesity, and Atherosclerosis.”

Atherosclerosis starts to develop when low-density lipoprotein (LDL) is oxidised by free radicals to generate oxLDL, which damages arterial walls and triggers repair mechanisms. The repair process involves the recruitment of monocytes to the damaged arterial walls, and their differentiation into macrophages that ingest oxLDL and accumulate cholesterol in the form of lipid droplets, leading to the formation of foam cells. Because the cells can’t process the oxLDL, they continue to grow and eventually rupture, depositing even more oxidized cholesterol in the arterial wall, and propagating further immune responses.

Studies by the Singapore team in engineered mice now suggest that Wip1 phosphatase promotes atherosclerosis, as well as diet-induced weight gain and fat accumulation. They found that genetic-knockout animals lacking ApoE and Wip1 put on far less weight when fed a high-fat western diet than ApoE knockouts that retained wild-type Wip1. In comparison with the wild-type Wip1 animals, the double knockouts had far less body fat and lighter livers with evidence of suppressed steatosis. They also ate less and expended more energy. Importantly, the ApoE/Wip1 knockout mice demonstrated higher usage of fat as an energy source...