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 PPARγ, 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 PPARγ 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. |