Tsukamoto Hide
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.
Keio J Med. 2005 Dec;54(4):190-2. doi: 10.2302/kjm.54.190.
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.
酒精性肝病（ALD）的特征是中性脂质在肝细胞中蓄积，导致微泡和大泡性脂肪变性以及气球样细胞变性。高热量饮食及由此导致的肥胖也会引起类似的变化，这在非酒精性脂肪性肝病（NAFLD）中很明显。因此，脂质在肝细胞中的蓄积是ALD和NAFLD的病理标志。相比之下，静止的肝星状细胞（HSC）的特征不仅在于细胞内含有维生素A，还含有甘油三酯，并且HSC激活与这些脂质的消耗有关。事实上，我们最近的研究表明，由PPARγ、LXRα和SREBP-1c介导的脂肪生成/脂质生成转录调控对于维持HSC的脂肪储存静止表型至关重要。这些脂肪生成转录因子的表达在活化的HSC中丧失，用脂肪细胞分化混合物处理细胞或PPARγ或SREBP-1c的异位表达会使活化细胞逆转至静止表型。在ALD和NAFLD小鼠模型的脂肪变性肝脏中，这些脂肪生成转录因子的表达被诱导，而正常对照肝脏则缺乏这种表达。因此，脂肪生成调控对于HSC静止至关重要，而它会使肝细胞发生脂肪变性。有趣的是，在ALD和NAFLD的脂肪生成条件下，HSC仍然被激活以导致纤维化。肝细胞和HSC中的这种脂肪悖论突出了脂肪在这两种相互依赖以维持稳态的细胞类型中的不同意义。这进一步表明，脂肪变性肝脏中的活化HSC可能存在胰岛素信号传导或脂肪生成调控缺陷。
