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The Propensity of t...
The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity
- Article/chapterEnglish2021
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LIBRIS-ID:oai:gup.ub.gu.se/306341
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https://gup.ub.gu.se/publication/306341URI
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https://doi.org/10.3390/ijms22116100DOI
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Subject category:art swepub-publicationtype
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In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving >= 50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by alpha-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.
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Carotti, S.
(author)
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Carpino, G.
(author)
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Mischitelli, M.
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Cantafora, A.
(author)
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Molinaro, AntonioGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory(Swepub:gu)xmolia
(author)
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Argenziano, M. E.
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Parisse, S.
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Corsi, A.
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Riminucci, M.
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Lai, Q.
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Mennini, G.
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Spadetta, G.
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Pugliese, F.
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Rossi, M.
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Morini, S.
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Gaudio, E.
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Corradini, S. G.
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Göteborgs universitetInstitutionen för medicin, avdelningen för molekylär och klinisk medicin
(creator_code:org_t)
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In:International Journal of Molecular Sciences: MDPI AG22:111661-65961422-0067
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Ferri, F.
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Carotti, S.
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Carpino, G.
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Mischitelli, M.
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Cantafora, A.
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Molinaro, Antoni ...
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Argenziano, M. E ...
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Parisse, S.
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Corsi, A.
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Riminucci, M.
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Lai, Q.
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Mennini, G.
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Spadetta, G.
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Pugliese, F.
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Rossi, M.
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Morini, S.
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Gaudio, E.
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Corradini, S. G.
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University of Gothenburg