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Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis.
Key, Chia-Chi C; Liu, Mingxia; Kurtz, C Lisa; Chung, Soonkyu; Boudyguina, Elena; Dinh, Timothy A; Bashore, Alexander; Phelan, Peter E; Freedman, Barry I; Osborne, Timothy F; Zhu, Xuewei; Ma, Lijun; Sethupathy, Praveen; Biddinger, Sudha B; Parks, John S.
Afiliação
  • Key CC; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Liu M; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Kurtz CL; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Chung S; Department of Nutrition and Health Sciences, University of Nebraska, Lincoln, NE 68588, USA.
  • Boudyguina E; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Dinh TA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bashore A; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Phelan PE; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
  • Freedman BI; Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Osborne TF; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
  • Zhu X; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Ma L; Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
  • Sethupathy P; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Biddinger SB; Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02062, USA.
  • Parks JS; Section on Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address: jparks@wakehealth.edu.
Cell Rep ; 19(10): 2116-2129, 2017 06 06.
Article em En | MEDLINE | ID: mdl-28591582
Plasma membrane (PM) free cholesterol (FC) is emerging as an important modulator of signal transduction. Here, we show that hepatocyte-specific knockout (HSKO) of the cellular FC exporter, ATP-binding cassette transporter A1 (ABCA1), leads to decreased PM FC content and defective trafficking of lysosomal FC to the PM. Compared with controls, chow-fed HSKO mice had reduced hepatic (1) insulin-stimulated Akt phosphorylation, (2) activation of the lipogenic transcription factor Sterol Regulatory Element Binding Protein (SREBP)-1c, and (3) lipogenic gene expression. Consequently, Western-type diet-fed HSKO mice were protected from steatosis. Surprisingly, HSKO mice had intact glucose metabolism; they showed normal gluconeogenic gene suppression in response to re-feeding and normal glucose and insulin tolerance. We conclude that: (1) ABCA1 maintains optimal hepatocyte PM FC, through intracellular FC trafficking, for efficient insulin signaling; and (2) hepatocyte ABCA1 deletion produces a form of selective insulin resistance so that lipogenesis is suppressed but glucose metabolism remains normal.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Colesterol / Hepatócitos / Lipogênese / Transportador 1 de Cassete de Ligação de ATP / Fígado Limite: Animals Idioma: En Revista: Cell Rep Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Colesterol / Hepatócitos / Lipogênese / Transportador 1 de Cassete de Ligação de ATP / Fígado Limite: Animals Idioma: En Revista: Cell Rep Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos