PublicaciĂłn: SECRETORY FACTORS FROM CALCIUM-SENSING RECEPTOR-ACTIVATED SW872 PRE-ADIPOCYTES INDUCE CELLULAR SENESCENCE AND A MITOCHONDRIAL FRAGMENTATION-MEDIATED INFLAMMATORY RESPONSE IN HEPG2 CELLS
Fecha
2023
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Resumen
ADIPOSE TISSUE INFLAMMATION IN OBESITY HAS A DELETERIOUS IMPACT ON ORGANS SUCH AS THE LIVER, ULTIMATELY LEADING TO THEIR DYSFUNCTION. WE HAVE PREVIOUSLY SHOWN THAT ACTIVATION OF THECALCIUM-SENSING RECEPTOR (CASR) IN PRE-ADIPOCYTES INDUCES TNF-? AND IL-1? EXPRESSION AND SECRETION; HOWEVER, IT IS UNKNOWN WHETHER THESE FACTORS PROMOTE HEPATOCYTE ALTERATIONS, PARTICULARLY PROMOTING CELL SENESCENCE AND/OR MITOCHONDRIAL DYSFUNCTION. WE GENERATED CONDITIONED MEDIUM (CM) FROM THE PRE-ADIPOCYTE CELL LINE SW872 TREATED WITH EITHER VEHICLE (CMVEH) OR THE CASR ACTIVATOR CINACALCET 2 ?M (CMCIN), IN THE ABSENCE OR PRESENCE OF THE CASR INHIBITOR CALHEX 231 10 ?M (CMCIN+CAL). HEPG2 CELLS WERE CULTURED WITH THESE CM FOR 120 H AND THEN ASSESSED FOR CELL SENESCENCE AND MITOCHONDRIAL DYSFUNCTION. CMCIN-TREATED CELLS SHOWED INCREASED SA-?-GAL STAINING, WHICH WAS ABSENT IN TNF-?- AND IL-1?-DEPLETED CM. COMPARED TO CMVEH, CMCIN ARRESTED CELL CYCLE, INCREASED IL-1? AND CCL2 MRNA, AND INDUCED P16 AND P53 SENESCENCE MARKERS, WHICH WAS PREVENTED BY CMCIN+CAL. CRUCIAL PROTEINS FOR MITOCHONDRIAL FUNCTION, PGC-1? AND OPA1, WERE DECREASED WITH CMCIN TREATMENT, CONCOMITANT WITH FRAGMENTATION OF THE MITOCHONDRIAL NETWORK AND DECREASED MITOCHONDRIAL TRANSMEMBRANE POTENTIAL. WE CONCLUDE THAT PRO-INFLAMMATORY CYTOKINES TNF-? AND IL-1? SECRETED BY SW872 CELLS AFTER CASR ACTIVATION PROMOTE CELL SENESCENCE AND MITOCHONDRIAL DYSFUNCTION, WHICH IS MEDIATED BY MITOCHONDRIAL FRAGMENTATION IN HEPG2 CELLS AND WHOSE EFFECTS WERE REVERSED WITH MDIVI-1. THIS INVESTIGATION PROVIDES NEW EVIDENCE ABOUT THE DELETERIOUS CASR-INDUCED COMMUNICATION BETWEEN PRE-ADIPOCYTES AND LIVER CELLS, INCORPORATING THE MECHANISMS INVOLVED IN CELLULAR SENESCENCE.
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pre-adipocyte, hepatocyte, cell senescence, calcium-sensing receptor
