Abstract
TGFβ signaling plays a major role in the reorganization of liver tissue upon injury and is an important driver of chronic liver disease. This is achieved by a deep impact on a cohort of cellular functions. To comprehensively assess the full range of affected metabolic functions, transcript changes of cultured mouse hepatocytes were analyzed with a novel method (ModeScore), which predicts the activity of metabolic functions by scoring transcript expression changes with 987 reference flux distributions, which yielded the following hypotheses. TGFβ multiplies down-regulation of most metabolic functions occurring in culture stressed controls. This is especially pronounced for tyrosine degradation, urea synthesis, glucuronization capacity, and cholesterol synthesis. Ethanol degradation and creatine synthesis are down-regulated only in TGFβ treated hepatocytes, but not in the control. Among the few TGFβ dependently up-regulated functions, synthesis of various collagens is most pronounced. Further interesting findings include: down-regulation of glucose export is postponed by TGFβ, TGFβ up-regulates the synthesis capacity of ketone bodies only as an early response, TGFβ suppresses the strong up-regulation of Vanin, and TGFβ induces re-formation of ceramides and sphingomyelin.
Highlights
TGFβ signaling is central in the late stages of liver regeneration [1]
We found that hepatocytes subjected to elevated TGFβ levels undergo substantial changes including its metabolic functions [1]
Isolated hepatocytes suffer from an immediate loss of function due to culture stress, which can partly be restored by a calf embryo medium and attachment to the collagen layer
Summary
TGFβ signaling is central in the late stages of liver regeneration [1]. Increased levels of TGFβ are an intermediate driver of chronic liver diseases [2] and represent a critical positive feedback loop in alcoholic liver disease [3]. We found that hepatocytes subjected to elevated TGFβ levels undergo substantial changes including its metabolic functions [1]. Isolated hepatocytes suffer from an immediate loss of function due to culture stress, which can partly be restored by a calf embryo medium and attachment to the collagen layer. The metabolism of mouse hepatocytes in culture differs quantitatively and qualitative aspects from hepatocytes in vivo [7,8], and the cytokine TGFβ is involved in this process [9]. Hepatocytes in culture are in a non-steady state, which is characterized by permanent functional changes, especially loss of metabolic functions, and the purpose of this study was to identify if and how the effects of TGFβ on hepatocytes in culture account for such outcome
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