Fat paradox in liver disease.
Alcoholic liver disease (ALD) is characterized by accumulation of neutral lipids in hepatocytes leading to micro and macro-vesicular steatosis and balloon cell degeneration. Hypercaloric alimentation and resultant obesity also cause similar changes as evident in non-alcoholic fatty liver disease (NAFLD). Thus, accumulation of lipids in hepatocytes is a pathologic hallmark of ALD and NAFLD. In contrast, quiescent hepatic stellate cells (HSC) are characterized by the intracellular content of not only vitamin A but also triglycerides, and HSC activation is associated with depletion of these lipids. In fact, our recent work demonstrates that adipogenic/ lipogenic transcriptional regulation rendered by PPARgamma, LXRa, and SREBP-1c is essential for the maintenance of the fat-storing, quiescence phenotype of HSC. Expression of these adipogenic transcription factors is lost in activated HSC and the treatment of the cells with the adipocyte differentiation cocktail or ectopic expression of PPARgamma or SREBP-1c causes a reversal of activated cells to the quiescent phenotype. In steatotic livers from ALD and NAFLD mouse models, the expression of these adipogenic transcription factors is induced while the normal control livers lack such expression. Thus, adipogenic regulation is essential for HSC quiescence while it makes hepatocytes steatotic. Interestingly, under the adipogenic conditions of ALD and NAFLD, HSC are still activated to cause fibrosis. This fat paradox in hepatocytes and HSC highlights contrasted significance of fat in these two cell types that depend on each other for their homeostatic control. It further suggests, activated HSC in steatotic livers may have defective insulin signaling or lipogenic regulation.
Tsukamoto
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Department of Pathology, Keck School of Medicine of the University of Southern California and the Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. htsukamo@usc.edu
D017667:Adipocytes / Q000473:pathology* / Q000502:physiology*; D005234:Fatty Liver / Q000473:pathology* / Q000503:physiopathology; D022781:Hepatocytes / Q000473:pathology* / Q000502:physiology*; D006801:Humans; D047495:PPAR gamma / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology
D047495:PPAR gamma