Wip1-knockout mice resist weight gain and develop less atherosclerosis when fed high-fat diet.

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.

The western diet-fed ApoE/Wip1 knockout animals also developed far fewer atherosclerotic lesions in their arteries than the ApoE4/wild-type Wip1 mice given the same food, and demonstrated lower blood pressure. Notably, there was far less free cholesterol and cholesteryl esters in their peritoneal macrophages.

Interestingly, concentrations of circulating plasma fatty acids and total cholesterol in fractions of HDL and LDL weren’t significantly different between the two genotypes. Rather, the lower level of atherosclerotic plaque formation in the double-knockout animals was related to reduced fat deposition, a mechanism dependent on the formation of foam cells. In fact, when the team incubated bone marrow–derived macrophages from both genotypes of mice with oxLDL, far fewer of the ApoE/Wip1-knockout macrophages accumulated cholesterol and formed into foam cells than the ApoE-knockout macrophages. “These data strongly suggest that foam cell formation is dependent on the presence of Wip1,” the authors write.

Previous work had indicated that Wip1 regulates P38MAPK and Atm-dependent signalling pathways. To try and identify a molecular basis for the anti-obesity and atherosclerosis-suppressing effects induced by Wip1 deficiency, the researchers either chemically inhibited or genetically knocked down Atm, p38, and p53 (Atm plays a key role in the activation of p53 in tumor suppression) in ApoE/Wip1-knockout macrophages evaluated. This indicated a role for Wip1-Atm signalling, as chemical inhibition of Atm or knockdown of just one Atm allele completely reversed the inhibitory effect of Wip1 deficiency on foam cell formation, whereas p38 and p53 inhibition had no effect .

The involvement of Atm signalling specifically was supported in vivo by the finding that Wip1/ApoE-deficient animals with just one deleted Atm allele gained weight, put on fat, and exhibited increased atherosclerosis when fed on a western diet, whereas complete p53 deletion had no effect. Further genetic manipulation of Wip1-deficient macrophages indicated that reduced foam cell formation was related to Atm-dependent suppression of the mTOR signalling pathway.

Atm and mTOR are key regulators of autophagy that have recently been implicated in controlling fat metabolism, so the team looked at whether the reduction in cholesterol accumulation and foam cell formation in Wip1-knockout macrophages was due to changes in LDL uptake or to cholesterol efflux. This set of experiments demonstrated that LDL uptake was the same for Wip1/ApoE-knockout macrophages and the ApoE knockouts with wild-type Wip1. In contrast, Wip1 deletion was associated with much higher cholesterol efflux.

“We propose that the Wip1-dependent control of autophagy and cholesterol efflux may provide avenues for treating obesity and atherosclerosis,” the authors conclude. “In this work we extended the previously identified role of Wip1 phosphatase in tumorigenesis to show that it is critically involved in regulating diet-induced fat accumulation and atherosclerosis, by demonstrating that Wip1 deletion prevents both conditions … In light of recent data showing features of defective autophagy in advanced stages of atherosclerosis, it would be interesting to know if Wip1 inactivation, conditionally or with a drug at later stages of atherosclerosis, would have a significant protective effect.” 

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