The Relationship Between Apoptosis and Non-Alcoholic Fatty Liver Disease: An Evolutionary Cornerstone Turned Pathogenic

Zusammenfassung

Neueste Daten favorisieren für die nichtalkoholische Fettleber ein pathogenetisches Modell, in dem der Apoptose bei der Initiierung der Leberentzündung und -fibrose eine bedeutende Rolle zukommt. Infolge primärer hepatischer und peripherer Insulinresistenz und konsekutiv alteriertem Glucose- und Fettsäuremetabolismus erfolgt in den Leberparenchymzellen eine vermehrte Akkumulation freier Fettsäuren. Diese sind in der Lage, die hepatozytäre Expression exozellulärer Death-Rezeptoren heraufzuregulieren und damit die zelluläre Vulnerabilität zu erhöhen. Damit können die Hepatozyten durch pro-apoptotische Stimuli zur Apoptose und zur Freisetzung von Entzündungsmediatoren stimuliert werden. Im chronischem Zustand führt dieser Prozess zur Aktivierung von sowohl hepatischen Sternzellen als auch Kupffer-Zellen, wodurch Apoptose und Entzündung mit Zellaktivierung im Rahmen eines circulus vitiosus aufrecht erhalten werden und letztlich zur pro-fibrotischen Kollagensynthese und -ablagerung führen.

Abstract

The data currently available favor a model for the pathogenesis of non-alcoholic fatty liver disease that is based on an apparent sequential relationship of intrahepatic apoptosis, inflammation and fibrogenesis. Based on both hepatic and peripheral insulin resistance, the hepatocellular accumulation of triglycerides, termed steatosis, initially leads to an altered metabolism of glucose and free fatty acids in the liver. In response, increased expression of death receptors in simple steatosis enhances the hepatocytes’ susceptibility for pro-apoptotic stimuli, thus eliciting excessive hepatocyte apoptosis and inflammation. Evidence indicates that these processes, if prolonged, activate both hepatic stellate and Kupffer cells, thus leading to a vicious circle in which apoptosis, inflammation, cellular activation, and collagen deposition are upregulated even further.

Schlüsselwörter

NAFLD - NASH - Apoptose - Entzündung - Fibrose - Entwicklung - Evolution

Key words

NAFLD - NASH - apoptosis - inflammation - fibrosis - development - evolution

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