Analysis of DGAT2 mutations reveals potential links between cancer and lipid droplet deregulation

Abstract 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.

(RAP).However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes.The etiology of CCI is multifactorial and the relative importance remains unclear.Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression and catabolism syndrome (PICS) have been observed in CCI after sepsis.Therefore, the purpose of this study was to compare serial PICS biomarkers in a) older (versus young) adults and b) older CCI (versus older RAP) patients to gain insight into underlying pathobiology of CCI in older adults.Methods: Prospective longitudinal study with young (≤ 45 years) and older (≥ 65 years) septic adults who were characterized by a) baseline predisposition, b) hospital outcomes, c) serial SOFA organ dysfunction scores over 14 days, d) Zubrod Performance status at three, six and 12-month follow-up and e) mortality over 12 months.Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS.Results: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status and mortality over 12 months.Additionally, older (versus young) and older CCI (versus older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism and anti-angiogenesis over 14 days after sepsis.Conclusion: Older (versus young) and older CCI (versus older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS.

UROLITHIN A ENHANCES MUSCLE PERFORMANCE IN ELDERLY AND POSITIVELY IMPACTS BIO-MARKERS LINKED TO CELLULAR HEALTH Sophia Liu, and David Marcinek, University of Washington, seattle, Washington, United States
Background: Aging is associated with decline in mitochondrial function and reduced exercise capacity.Urolithin A (UA) is a natural gut metabolite shown to stimulate mitophagy and improve muscle function in aged animals, and induce mitochondrial gene expression in elderly.Purpose: Investigate if oral administration of UA improved walking distance (6MWT), muscle fatigue resistance in hand (FDI) and leg (TA) muscles, and had an impact on plasma biomarkers.Method: We conducted a randomized, double-blind, placebo-controlled study (NCT03283462) in elderly subjects (65-90 yrs.) supplemented daily with 1000mg UA or placebo for 4 months.128 subjects were screened and 66 randomized.6MWT and ATPmax via MRS were assessed at baseline and at 4 months.Muscle fatigue tests and plasma analysis of biomarkers were assessed at baseline, 2 and 4 months.Results: UA significantly improved muscle endurance (i.e., change in number of muscle contractions from baseline) in two different muscles (hand: PL 11.6 ±147.5, UA 95.3 ± 115.5; and leg: PL 5.7± 127.1, UA 41.4 ±65.5) compared with placebo at 2-months.Plasma levels of several acylcarnitines, ceramides and C-reactive-protein were decreased by UA at the end-of study.6MWT distance (PL 42.5 ± 73.3 m, UA 60.8± 67.2 m) and ATPmax increased in both groups from baseline (PL 13.7±31.4%,UA19.4± 56.8%) with UA supplemented group exhibiting greater improvements, although these were not statistically different between groups.Conclusion: UA supplementation improved muscle endurance, metabolic and inflammatory plasma biomarkers after 2-months, suggesting that UA can have a positive impact on muscle and cellular health in the elderly.

ith UA supplemented group exhibiting greater improvements, although these were not statistically different between groups.Conclusion: UA supplementation improved muscle endurance, metabolic and inflammator
plasma biomarkers after 2-months, suggesting that UA can have a positive impact on muscle and cellular health in the elderly.


Session 9095 (Poster)


Biology of Aging: Computational and Systems Approaches to Geroscience


ANALYSIS OF DGAT2 MUTATIONS REVEALS POTEN-TIAL LINKS BETWEEN CANCER AND LIPID DROPLET DEREGULATION Meghan Graber, and Hayley Barta, Xavier University, Cincinnati, Ohio, United States

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, alth

ANALYSIS OF DGAT2 MUTATIONS REVEALS POTEN-TIAL LINKS BETWEEN CANCER AND LIPID DROPLET DEREGULATION Meghan Graber, and Hayley Barta, Xavier University, Cincinnati, Ohio, United States
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.

, 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 fu
ction may be more complex than previously appreciated.


ASSOCIATION OF GRIMAGE DNA METHYLATION COMPONENTS AND 2-YEAR MORTALITY IN THE HEALTH AND RETIREMENT STUDY



Helen Meier, 1 Colter Mitchell, 2 Eileen Crimmins, 3 Bharat Thyagarajan, 4 and Jessica Faul, 2 1.University of Michigan, Ann Arbor, Michigan, United States, 2. University of Michigan, University of Michigan, Michigan, United States, 3. University of Southern California, Los Angeles, California, United States, 4. University of Minnesota, Minneapolis, Minnesota, United States DNA methylation (DNAm) patterns related to age and aging phenotypes (i.e., epigenetic clocks) are of growing interest as indicators of biological age and risk of negative health outcomes.We investigated associations between the components of GrimAge, an epigenetic clock estimated from DNAm patterns for seven blood protein levels and smoking pack years, and 2-year mortality in the Health and

Innovation inAging, 2021, Vol. 5, No. S1

ASSOCIATION OF GRIMAGE DNA METHYLATION COMPONENTS AND 2-YEAR MORTALITY IN THE HEALTH AND RETIREMENT STUDY
Helen Meier, 1 Colter Mitchell, 2 Eileen Crimmins, 3 Bharat Thyagarajan, 4 and Jessica Faul, 2 1.University of Michigan, Ann Arbor, Michigan, United States, 2. University of Michigan, University of Michigan, Michigan, United States, 3. University of Southern California, Los Angeles, California, United States, 4. University of Minnesota, Minneapolis, Minnesota, United States DNA methylation (DNAm) patterns related to age and aging phenotypes (i.e., epigenetic clocks) are of growing interest as indicators of biological age and risk of negative health outcomes.We investigated associations between the components of GrimAge, an epigenetic clock estimated from DNAm patterns for seven blood protein levels and smoking pack years, and 2-year mortality in the Health and