title: Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis?
abstract: Chronic liver disease causes significant morbidity and mortality through progressive fibrosis, cirrhosis, and liver cancer. The classical theory of fibrogenesis has hepatic stellate cells (HSCs) as the principal and only significant source of abnormal extracellular matrix (ECM). Further, HSCs have the major role in abnormal ECM turnover. It is the death of hepatocytes, as the initial target of injury, that initiates a sequence of events including the recruitment of inflammatory cells and activation of HSCs. Following this initial response, the ongoing insult to hepatocytes is regarded as perpetuating injury, but otherwise, hepatocytes are regarded as "victims" and "bystanders" in progressive fibrosis. Recent developments, however, challenge this view and suggest the concept of the hepatocyte being an active participant in liver injury. It is clear now that hepatocytes undergo phenotypic changes, adapt to injury, and react to the altered microenvironment. In this review, we describe studies showing that hepatocytes contribute to progressive fibrosis by direct manipulation of the surrounding ECM and through signaling to effector cells, particularly HSCs and intrahepatic immune cells. Together, these findings suggest an active "accomplice" role for the hepatocyte in progressive liver fibrosis and highlight novel pathways that could be targeted for development of future anti-fibrotic therapies.
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tu
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Calabro
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Aimei
authors.initials: A
authors.lastname: Lee
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Maczurek
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Budzinska
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Warner
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Susan V
authors.initials: SV
authors.lastname: McLennan
authors.affiliation: Liver Injury and Cancer, Centenary Institute, Sydney, New South Wales, Australia.|Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|A. W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Shackel
mesh_terms: D016923:Cell Death; D018450:Disease Progression; D005109:Extracellular Matrix; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D008115:Liver Regeneration
keywords: EMMPRIN; cell and molecular biology; hepatic inflammation; hepatology; liver fibrogenesis; liver immunobiology; liver regeneration; matrix metalloproteinases; stellate cell biology