DGAT2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation. Cancer cells exhibit altered lipid metabolism and mutations in DGAT2 may contribute to this state. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all cancer genetic DGAT2 alterations, including mutations, copy number variations and gene expression. We find that several DGAT2 mutations fall within the catalytic site of the enzyme. Using the Variant Effect Scoring Tool (VEST), we identify multiple mutations with a high likelihood of contributing to cellular transformation. We also found that D222V is a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease. Remarkably, Y223H has not been detected in cancers, suggesting that it is inhibitory to cancer progression. We also identify several single nucleotide polymorphisms (SNP) with high VEST scores, indicating that certain alleles in human populations have a pathogenic predisposition. Most mutations do not correlate with a change in gene expression, nor is gene expression dependent on high allele copy number. However, we did identify eight alleles with high expression levels, suggesting that at least in certain cases, the excess DGAT2 gene product is not inhibitory to cellular proliferation. This work uncovers unknown functions of DGAT2 in cancers and suggests that its role may be more complex than previously appreciated.

Lipids are essential for cell growth and maintenance, intracellular signaling, and cellular energetics. When exposed to environmental insults, cells activate lipid metabolism programs that facilitate the response, recovery, and exit from stressful conditions. Failure to regulate lipid storage and utilization is associated with accelerated aging, which compounds genomic instability. In this study, we test the physiological consequences of disruptions to three lipid regulator genes frequently found to be mutated in human cancers. Since the products of these genes show functional homology in fission yeast, we examine how lipid deregulation by two enzymes (Dga1DGAT2 and Cut6ACC) and one transcription factor (Sre1SREBF1) influence the response to genotoxic stress in this organism. Using microscopy quantification of lipid staining, we observe abnormal homeostatic control of lipid levels in cells lacking Dga1, Cut6, and Sre1. These phenotypes are enhanced in sub-lethal doses of DNA damage (UV-C light) and are associated with altered cell fitness and proliferation. Furthermore, in response to genotoxicity, these lipid regulator mutants exhibit disrupted nuclear segregation, abnormal cell dimensions, and altered lifespan. These data suggest functional mechanisms that may contribute to the deregulated metabolic and physiological environments of prematurely aged cells and of tumors in human cancers.

Diacylglycerol O-acyltransferase 2 is a transmembrane protein encoded by the DGAT2 gene that functions in lipid metabolism, triacylglycerol synthesis, and lipid droplet regulation. Since cancer cells exhibit altered lipid metabolism, it has been proposed that mutations in DGAT2 may contribute to this state. Using data from the Catalogue of Somatic Mutations in Cancer (COSMIC), we analyzed all reported DGAT2 mutations in human cancers. Bioinformatics analyses were performed to highlight the connections between age, pathogenicity, and cancer tissue type. Mutations are generally associated with samples from older individuals, except for those in glioblastomas which occur earlier. We also found that several DGAT2 mutations fall within the catalytic site of the enzyme and may affect enzyme function. Thus, these mutations may contribute to altered cancer metabolism. We identified D222V as a mutation hotspot neighboring a previously discovered Y223H mutation that causes Axonal Charcot-Marie-Tooth disease. Remarkably, Y223H has not been detected in cancers indicating it is inhibitory to cancer progression. Further analysis showed that most mutations do not affect DGAT2 gene expression suggesting this change is not a major contributor to cancer development. Intriguingly, although most cancers are characterized by low DGAT2 gene expression, some show high expression levels, indicating that, at least in certain cases, over-expression is not inhibitory to cellular proliferation. This work uncovers unknown roles of DGAT2 in cancers and suggests that its function may be more complex than previously appreciated.

Salt-sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen presenting cells (APCs), resulting in high blood pressure, but the mechanisms are not known. Here, we hypothesized that APC-specific JAK2 expression contributes to SSBP. We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt, and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP after a two week anti-hypertensive drug washout period. Here we found that expression of the genes of the JAK2 pathway mirrored changes in blood pressure after salt-loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11C+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acts downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and pro-inflammatory cytokine IL-6 in renal APCs, which activate T cells. This results in the production of IL-17A, IL-6, and TNF-⍺. Our findings reveal APC JAK2 signaling as a potential target for the treatment of SSBP.