Project Grant R56DK136596

ROLE OF YY1 IN PROMOTING HEPATIC INSULIN RESISTANCE, HYPERGLYCEMIA AND NAFLD - MODIFIED PROJECT SUMMARY/ABSTRACT SECTION TYPE 2 DIABETES (T2D) AND METABOLIC DYSFUNCTION-ASSOCIATED FATTY LIVER DISEASE (MAFLD) ARE TWO HIGHLY-ASSOCIATED METABOLIC DISORDERS. IT IS WELL-DOCUMENTED THAT AFRICAN AMERICANS ARE 60% MORE LIKELY TO DEVELOP T2D THAN NON-HISPANIC WHITES. MULTIPLE FACTORS CONTRIBUTE TO THESE DISPARITIES, INCLUDING BIOLOGICAL AND CLINICAL FACTORS, AS WELL AS HEALTH SYSTEM AND SOCIAL FACTORS. HOWEVER, AVAILABLE EVIDENCE OF ENVIRONMENTAL FACTORS ARE NOT ENOUGH TO EXPLAIN THIS SIGNIFICANT T2D DISPARITIES BETWEEN AFRICAN AMERICANS AND NON-HISPANIC WHITES. OUR DATABASE MINING IDENTIFIED A SEQUENCE VARIANT (RS142619613) WITHIN THE CODING REGION OF YY1 GENE (YIN YANG 1). RS142619613 OCCURS MAINLY IN AFRICAN AMERICANS. THIS NUCLEOTIDE VARIANT (G-C) LEADS TO GLU47ASP MISSENSE MUTATION, WHICH SIGNIFICANTLY INCREASED STABILITY AND TRANSCRIPTIONAL ACTIVITY OF YY1. WE FURTHER ESTABLISHED YY1 AS A TRANSCRIPTION ACTIVATOR OF MIR-23B/27B/24. MIR-23B/27B/24 SELECTIVELY DROVE AKT PHOSPHORYLATION BUT PREVENTED PHOSPHORYLATION OF FOXO1, THEREBY PROMOTING DE NOVO LIPOGENESIS (DNL) AND GLUCONEOGENESIS. PHENOTYPICALLY, ANTAGONIZING MIR-23B/27B/24 ALLEVIATED HEPATIC INSULIN RESISTANCE, HEPATOSTEATOSIS, HYPERGLYCEMIA AND MASH. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT RS142619613, BY AUGMENTING THE YY1-MIR-23B/27B/24 AXIS, SELECTIVELY DRIVES PHOSPHORYLATION OF AKT AND PREVENTS PHOSPHORYLATION OF FOXO1, THEREBY SHIFTING THE METABOLIC PROGRAM OF THE LIVER TOWARDS INCREASED GLUCONEOGENESIS AND DNL AND EXACERBATING HEPATIC INSULIN RESISTANCE, HYPERGLYCEMIA AND HEPATOSTEATOSIS. THE OBJECTIVE OF THIS R56 PROJECT IS TO ELUCIDATE THE ROLE OF MIR-23B/27B/24 IN PROMOTING MASH DEVELOPMENT AND EVALUATE THE EFFECT OF RS142619613 ON LIPID AND GLUCOSE HOMEOSTASIS IN HUMAN HEPATOCYTES. OUR LONG-TIME GOAL IS TO EXPLAIN THE HIGHER INCIDENCE OF T2D AND MAFLD IN AFRICAN AMERICANS AND DEVELOP YY1 AND MIR-23B/27B/24 AS POTENTIAL THERAPEUTIC TARGETS AGAINST BOTH CONDITIONS. TWO SPECIFIC AIMS ARE DESIGNED TO TEST OUR HYPOTHESIS IN THIS R56 PROJECT. IN AIM 1, WE WILL ESTABLISH THE ROLE OF MIR-23B/27B/24 IN PROMOTING HEPATIC INFLAMMATION AND FIBROSIS AND EVALUATE THE IMPACTS OF MIR-23B/27B/24 KNOCKDOWN AND LIVER-SPECIFIC EXPRESSION OF WWC1 ON FOOD INTAKE, BODY WEIGHT, GLUCOSE HOMEOSTASIS, AND LIPID HOMEOSTASIS. COMPLETION OF THIS AIM WILL ESTABLISH GAIN-OF MIR-23B/27B/24 IN PROMOTING MASH. IN AIM 2, WE WILL ASSESS THE ROLE OF RS142619613 IN DISRUPTING LIPID AND GLUCOSE HOMEOSTASIS IN HUMAN HEPATOCYTES. UNDERSTANDING HOW T2D AND MAFLD DEVELOPS IS OF CRITICAL IMPORTANCE TO DESIGN THERAPEUTIC STRATEGIES TO COMBAT BOTH CHRONIC ILLNESS. THE RESULTS WILL PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS OF THE HIGHER PREVALENCE OF T2D IN AFRICAN AMERICANS, WHICH MAY LEAD TO RATIONAL THERAPEUTIC STRATEGIES FOR T2D.