Role of SMPDL3B in obesity-associated non-alcoholic fatty liver disease

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Principal Investigator: Shuxia  Wang
Organization: UNIVERSITY OF KENTUCKY
Fiscal Year: 2023
Award: $478,167
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

Obesity is an independent risk factor for development of non-alcoholic fatty liver disease (NAFLD). With the
epidemic burden of obesity and metabolic diseases, NAFLD occurrence is steadily rising, along with the need
for therapeutic options of this disease. Preliminary data from rodent and human studies provide strong
evidence to support the hypothesis that monocyte/macrophage-derived TSP1 in obesity downregulates liver
macrophage SMPDL3B and this downregulation feeds back to increase TSP1 binding to its receptor-CD36.
This positive feedback loop together with SMPDL3B’s action on TLR pathways further amplifies liver
macrophage pro-inflammatory signaling and leads to NAFLD progression. In this proposal, how SMPDL3B
regulates CD36 function and then TSP1-CD36 dependent pro-inflammatory signaling in macrophages will be
determined in Aim 1. The in vivo importance of macrophage SMPDL3B in NAFLD development and
progression in both animal models and human liver organoids will be determined in Aim 2. Whether specific
blockade of TSP1/CD36 interaction upregulates liver macrophage SMPDL3B and attenuates liver pro-
inflammatory signaling and NAFLD development and progression will be determined in Aim 3. Completing
these studies will provide novel information on the mechanisms by which suppressed macrophage SMPDL3B
enhances liver macrophage pro-inflammatory signaling and its critical role in the progression of obesity-
associated NAFLD to NASH. Further, testing a novel therapeutic application of a peptide nanoparticle
conjugate to block TSP1/CD36 interaction in obesity-associated NASH in vivo will have translational
significance.

Terms: <3-D><3-Dimensional><3D><Acids><Affect><Animal Model><Animal Models and Related Studies><Animals><Attenuated><Back><Binding><Blood monocyte><CD36><CD36 Antigens><CD36 Fatty Acid Transporter><CD36 gene><Cell Communication and Signaling><Cell Membrane Lipid Rafts><Cell Membrane Lipids><Cell Signaling><Cell membrane><Ceramides><Cytoplasmic Membrane><Data><Development><Diet><Disease><Disease Progression><Disorder><Dorsum><Down-Regulation><Epidemic><Fatty Liver><Feedback><Feeds><Fibrosis><GP3B><GP4><GPI Membrane Anchors><GPIV><GPIV Platelet Glycoprotein><Glycoinositol Phospholipid Membrane Anchor><Glycosyl-Phosphatidylinositol Membrane Protein Anchors><Glycosylphosphatidylinositol Anchors><Hepatic Disorder><Homolog of Drosophila TOLL><Human><In Vitro><Infiltration><Inflammation><Inflammatory><Intracellular Communication and Signaling><Knock-out><Knockout><Knowledge><Kupffer Cells><Lipids><Liver><Liver Fibrosis><Liver Steatosis><Liver diseases><Macrophage><Macrophage Activation><Maps><Marrow monocyte><Mediating><Membrane Lipids><Membrane Microdomains><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Diseases><Metabolic Disorder><Modeling><Modern Man><Modification><Molecular Interaction><Mφ><NAFLD><NASH><Obesity><Organoids><Pathogenesis><Pathway interactions><Patients><Peptides><Phenotype><Plasma Membrane><Process><Production><Proteins><Receptor Protein><Reducing diet><Risk Factors><Rodent><Rodentia><Rodents Mammals><Role><SCARB3><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Sphingomyelin Cholinephosphohydrolase><Sphingomyelin Cleaving Enzyme><Sphingomyelin Phosphodiesterase><Sphingomyelinase><Sphingomyelinase C><Stellate Sinusoidal Macrophage><Surface Proteins><TLR4><TLR4 gene><TSP-1><TSP1><Testing><Therapeutic><Thesaurismosis><Thrombospondin 1><Thrombospondin Receptors><Toll Homologue><Western World><adiposity><attenuate><attenuates><biological signal transduction><chronic hepatic disease><chronic hepatic disorder><chronic liver disease><chronic liver disorder><corpulence><cytokine><develop therapy><developmental><diets><fibrotic liver><hepatic body system><hepatic disease><hepatic fibrosis><hepatic organ system><hepatic steatosis><hepatopathy><hepatosteatosis><in vitro Model><in vivo><intervention development><knock-down><knockdown><lipid raft><liver disorder><liver macrophage><metabolism disorder><model of animal><monocyte><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><non-alcohol fatty liver><non-alcohol fatty liver disease><non-alcohol induced steatohepatitis><non-alcoholic fatty liver><non-alcoholic fatty liver disease><non-alcoholic liver disease><non-alcoholic steato-hepatitis><non-alcoholic steatohepatitis><nonalcohol fatty liver><nonalcoholic fatty liver><nonalcoholic fatty liver disease><nonalcoholic steato-hepatitis><nonalcoholic steatohepatitis><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><obesity intervention><obesity therapy><obesity treatment><overexpress><overexpression><pathway><peripheral blood><plasmalemma><receptor><recruit><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy development><three dimensional><toll-like receptor 4><treatment development>