A Functional, Genome-wide Evaluation of Liposensitive Yeast Identifies the “RE2 Required for Viability” (ARV1) Gene Product as a Major Component of Eukaryotic Fatty Acid Resistance

Abstract

Background: Obesity-related diseases result from accumulation of lipids in nonadipose tissues. Results: Mutations in 167 yeast genes confer fatty acid sensitivity. Loss of yeast and mammalian ARV1 results in pronounced lipid hypersensitivity, lipoapoptosis, and reduced triglyceride synthesis. Conclusion: 75 evolutionarily conserved components of obesity-related disorders were identified. Significance: Understanding lipid sensitivity may lead to treatment of numerous human metabolic diseases.

Knockdown of triglyceride synthesis does not enhance palmitate lipotoxicity or prevent oleate-mediated rescue in rat hepatocytes

“…However, the results of this study appear to contradict previous results in other cell types, such as the study by Listenberger et al that demonstrated increased cellular sensitivity to oleate in response to DGAT knockout in MEFs [15]. Additional studies involving yeast screens for fatty acid sensitive strains support those results [48, 49]. There are several possible explanations for these seemingly contradictory findings.…”

“…Additionally, these studies utilized complete knockouts of lipogenic enzymes, which may lead to non-physiological accumulation of lipid intermediates or death by a mechanism that is completely different from the mechanism of palmitate lipotoxicity in normal hepatocytes. Another complication is that some of the yeast knockouts, such as the ARV1 mutant [49], exhibited high levels of basal ER stress in the absence of fatty acid treatments [50]. Further studies are needed to identify the important differences between these lipotoxicity models and our own, in order to fully elucidate the mechanism by which OA can prevent PA-induced lipotoxicity in hepatocytes.…”

Control of membrane fluidity: the OLE pathway in focus

“…Consequently, a failure to produce unsaturated membrane lipids can cause a severe reorganization of organelle abundance and morphology, and -in extreme casescell death (Zhang et al, 1999;Pineau et al, 2009;Preston et al, 2009;Hapala et al, 2011;Surma et al, 2013). The overproduction of unsaturated lipids, however, is equally harmful and can cause fatty acid-induced necrosis (Richly et al, 2005;Rockenfeller et al, 2010;Hapala et al, 2011;Eisenberg and Buettner, 2014;Ruggles et al, 2014). The best-characterized eukaryotic surveillance system of lipid saturation is the OLE pathway (Covino et al, 2016;Ernst et al, 2016).…”

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

“…Our results strongly suggest that complete loss of Arv1 protects mice from acquiring MetS and NAFLD in response to a HFD challenge. While it is still up for debate as to what is the function of ARV1 (13)(14)(15)18,19,41), evidence is accumulating that suggests it's involvement in maintaining proper sterol distribution (16,20,42,43).…”

“…They contain fragmented vacuoles and a disrupted organelle phenotype (17), which most likely activates the unfolded protein response (18). Null cells are hypersensitive to fatty acid supplementation (19), suggesting that Arv1 also regulates fatty acid metabolism. Thus, yeast Arv1 has a major role in regulating lipid synthesis, metabolism, and homeostasis, and is needed to rescue cells when these processes become perturbed.…”