Browsing by Subject "Lipid metabolism"
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Item Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer(SpringerNature, 2016-12-15) Li, J.; Gu, D.; Lee, SS-Y.; Song, B.; Bandyopadhyay, S.; Chen, S.; Konieczny, SF.; Ratliff, TL.; Liu, X.; Xie, J.; Cheng, J-X.; Department of Pediatrics, IU School of MedicineCancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.Item Autophagy in liver diseases: A matter of what to remove and whether to keep(KeAi Communications, 2018-09) Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of MedicineItem Cellular membranes and lipid-binding domains as attractive targets for drug development(Bentham Science Publishers, 2008-08) Sudhahar, C.G.; Haney, R.M.; Xue, Y.; Stahelin, R.V.; Biochemistry and Molecular Biology, School of MedicineInterdisciplinary research focused on biological membranes has revealed them as signaling and trafficking platforms for processes fundamental to life. Biomembranes harbor receptors, ion channels, lipid domains, lipid signals, and scaffolding complexes, which function to maintain cellular growth, metabolism, and homeostasis. Moreover, abnormalities in lipid metabolism attributed to genetic changes among other causes are often associated with diseases such as cancer, arthritis and diabetes. Thus, there is a need to comprehensively understand molecular events occurring within and on membranes as a means of grasping disease etiology and identifying viable targets for drug development. A rapidly expanding field in the last decade has centered on understanding membrane recruitment of peripheral proteins. This class of proteins reversibly interacts with specific lipids in a spatial and temporal fashion in crucial biological processes. Typically, recruitment of peripheral proteins to the different cellular sites is mediated by one or more modular lipid-binding domains through specific lipid recognition. Structural, computational, and experimental studies of these lipid-binding domains have demonstrated how they specifically recognize their cognate lipids and achieve subcellular localization. However, the mechanisms by which these modular domains and their host proteins are recruited to and interact with various cell membranes often vary drastically due to differences in lipid affinity, specificity, penetration as well as protein-protein and intramolecular interactions. As there is still a paucity of predictive data for peripheral protein function, these enzymes are often rigorously studied to characterize their lipid-dependent properties. This review summarizes recent progress in our understanding of how peripheral proteins are recruited to biomembranes and highlights avenues to exploit in drug development targeted at cellular membranes and/or lipid-binding proteins.Item Deletion of miR‐33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice(Wiley, 2024) Tate, Mason; Wijeratne, H. R. Sagara; Kim, Byungwook; Philtjens, Stéphanie; You, Yanwen; Lee, Do-Hun; Gutierrez, Daniela A.; Sharify, Daniel; Wells, Megan; Perez-Cardelo, Magdalena; Doud, Emma H.; Fernandez-Hernando, Carlos; Lasagna-Reeves, Cristian; Mosley, Amber L.; Kim, Jungsu; Biochemistry and Molecular Biology, School of MedicineIntroduction: Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA-33 (miR-33)-mediated regulation of this ABCA1-APOE pathway affects phenotypes of an amyloid mouse model. Methods: We generated mir-33+/+;APP/PS1 and mir-33-/-;APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR-33 in microglial migration and amyloid beta (Aβ) phagocytosis. Results: Mir-33 deletion increases ABCA1 levels and reduces Aβ accumulation and glial activation. Multi-omics studies suggested miR-33 regulates the activation and migration of microglia. We confirm that the inhibition of miR-33 significantly increases microglial migration and Aβ phagocytosis. Discussion: These results suggest that miR-33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Highlights: Loss of microRNA-33 (miR-33) increased ABCA1 protein levels and the lipidation of apolipoprotein E. Loss of miR-33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis. mRNAs and proteins dysregulated by miR-33 loss relate to microglia and Alzheimer's disease. Inhibition of miR-33 increased microglial migration and Aβ phagocytosis in vitro.Item Hepatic Fat in Participants With and Without Incident Diabetes in the Diabetes Prevention Program Outcome Study(The Endocrine Society, 2021) Goldberg, Ronald B.; Tripputi, Mark T.; Boyko, Edward J.; Budoff, Matthew; Chen, Zsu-Zsu; Clark, Jeanne M.; Dabelea, Dana M.; Edelstein, Sharon L.; Gerszten, Robert E.; Horton, Edward; Mather, Kieren J.; Perreault, Leigh; Temprosa, Marinella; Wallia, Amisha; Watson, Karol; Irfan, Zeb; Medicine, School of MedicineContext: There is little information about fatty liver in prediabetes as it transitions to early diabetes. Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP). Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed. Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence. Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted.Item Inhibition of stearoyl-CoA desaturases suppresses follicular help T- and germinal center B- cell responses(Wiley, 2020-07) Son, Young Min; Cheon, In Su; Goplen, Nick P.; Dent, Alexander L.; Sun, Jie; Microbiology and Immunology, School of MedicineStearoyl-CoA desaturases (SCD) are endoplasmic reticulum (ER)-associated enzymes that catalyze the synthesis of the monounsaturated fatty acids (MUFAs). As such, SCD play important roles in maintaining the intracellular balance between saturated fatty acid (SFAs) and MUFAs. The roles of SCD in CD4+ T-helper cell responses are currently unexplored. Here, we have found that murine and human follicular helper T (TFH ) cells express higher levels of SCD compared to non-TFH cells. Further, the expression of SCD in TFH cells is dependent on the TFH lineage-specification transcription factor BCL6. We found that the inhibition of SCD impaired TFH cell maintenance and shifted the balance between TFH and follicular regulatory T (TFR ) cells in the spleen. Consequently, SCD inhibition dampened germinal center B-cell responses following influenza immunization. Mechanistically, we found that SCD inhibition led to increased ER stress and enhanced TFH cell apoptosis in vitro and in vivo. These results reveal a possible link between fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, autoimmunity.Item Investigation of the Lipid Binding Properties of the Marburg Virus Matrix Protein VP40(American Society for Microbiology, 2015-12-30) Wijesinghe, Kaveesha J.; Stahelin, Robert V.; Department of Biochemistry & Molecular Biology, IU School of MedicineMarburg virus (MARV), which belongs to the virus family Filoviridae, causes hemorrhagic fever in humans and nonhuman primates that is often fatal. MARV is a lipid-enveloped virus that during the replication process extracts its lipid coat from the plasma membrane of the host cell it infects. MARV carries seven genes, one of which encodes its matrix protein VP40 (mVP40), which regulates the assembly and budding of the virions. Currently, little information is available on mVP40 lipid binding properties. Here, we have investigated the in vitro and cellular mechanisms by which mVP40 associates with lipid membranes. mVP40 associates with anionic membranes in a nonspecific manner that is dependent upon the anionic charge density of the membrane. These results are consistent with recent structural determination of mVP40, which elucidated an mVP40 dimer with a flat and extensive cationic lipid binding interface. IMPORTANCE Marburg virus (MARV) is a lipid-enveloped filamentous virus from the family Filoviridae. MARV was discovered in 1967, and yet little is known about how its seven genes are used to assemble and form a new viral particle in the host cell it infects. The MARV matrix protein VP40 (mVP40) underlies the inner leaflet of the virus and regulates budding from the host cell plasma membrane. In vitro and cellular assays in this study investigated the mechanism by which mVP40 associates with lipids. The results demonstrate that mVP40 interactions with lipid vesicles or the inner leaflet of the plasma membrane are electrostatic but nonspecific in nature and are dependent on the anionic charge density of the membrane surface. Small molecules that can disrupt lipid trafficking or reduce the anionic charge of the plasma membrane interface may be useful in inhibiting assembly and budding of MARV.Item Long Non-coding RNA in Liver Metabolism and Disease: Current Status(Elsevier, 2017-09) Zhao, Yulan; Wu, Jianguo; Liangpunsakul, Suthat; Wang, Li; Medicine, School of MedicineLong non-coding RNAs (lncRNAs) are comprised of RNA transcripts exceeding 200 nucleotides in length but lacking identifiable open reading frames (with rare exceptions). Herein, we highlight emerging evidence demonstrating that lncRNAs are critical regulators of liver metabolic function and diseases. We summarize current knowledges about dysregulated lncRNAs and outline the underlying molecular mechanisms by which lncRNAs control hepatic lipid ad glucose metabolism, as well as cholestatic liver disease. lncLSTR, Lnc18q22.2, SRA, HULC, MALAT1, lncLGR, MEG3, and H19, lncHR1, lnc-HC, APOA1-AS, DYNLRB2-2, and LeXis are included in the discussion.Item Lysosomal Acid Lipase Is Required for Donor T Cells to Induce Graft-versus-Host Disease(Cell Press, 2020-10-27) Nguyen, Hung D.; Ticer, Taylor; Bastian, David; Kuril, Sandeepkumar; Li, Hong; Du, Hong; Yan, Cong; Yu, Xue-Zhong; Pathology and Laboratory Medicine, School of MedicineGraft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT). Lysosomal acid lipase (LAL) mediates the intrinsic lipolysis of cells to generate free fatty acids (FFAs), which play an essential role in the development, proliferation, and function of T cells. Here, we find that LAL is essential for donor T cells to induce GVHD in murine models of allo-HCT. Specifically, LAL is required for donor T cell survival, differentiation, and alloreactivity in GVHD target organs, but not in lymphoid organs. LAL induces the differentiation of donor T cells toward GVHD pathogenic Th1/Tc1 and Th17 while suppressing regulatory T cell generation. LAL-/- T cells succumb to oxidative stress and become anergic in target organs. Pharmacologically targeting LAL effectively prevents GVHD development while preserving the GVL activity. Thus, the present study reveals the role of LAL in T cell alloresponse and pathogenicity and validates LAL as a target for controlling GVHD and tumor relapse after allo-HCT.Item Metabolomic Analysis Uncovers Energy Supply Disturbance as an Underlying Mechanism of the Development of Alcohol‐Associated Liver Cirrhosis(Wiley, 2021-03-08) Huang, Ying; Niu, Ming; Jing, Jing; Zhang, Zi-teng; Zhao, Xu; Chen, Shuai-shuai; Li, Shan-shan; Shi, Zhu; Huang, Ang; Zou, Zheng-Sheng; Yu, Yue-cheng; Xiao, Xiao-he; Liangpunsakul, Suthat; Wang, Jia-bo; Medicine, School of MedicineAlcohol-associated liver disease (ALD) is caused by alcohol metabolism's effects on the liver. The underlying mechanisms from a metabolic view in the development of alcohol-associated liver cirrhosis (ALC) are still elusive. We performed an untargeted serum metabolomic analysis in 14 controls, 16 patients with ALD without cirrhosis (NC), 27 patients with compensated cirrhosis, and 79 patients with decompensated ALC. We identified two metabolic fingerprints associated with ALC development (38 metabolites) and those associated with hepatic decompensation (64 metabolites) in ALC. The cirrhosis-associated fingerprint (eigenmetabolite) showed a better capability to differentiate ALC from NC than the aspartate aminotransferase-to-platelet ratio index score. The eigenmetabolite associated with hepatic decompensation showed an increasing trend during the disease progression and was positively correlated with the Model for End-Stage Liver Disease score. These metabolic fingerprints belong to the metabolites in lipid metabolism, amino acid pathway, and intermediary metabolites in the tricarboxylic acid cycle. Conclusion: The metabolomic fingerprints suggest the disturbance of the metabolites associated with cellular energy supply as an underlying mechanism in the development and progression of alcoholic cirrhosis.