What is known: Liver-to-body mass-ratio is held constant by a phenomenon named the ?hepatostat? [1]. When liver is damaged, an ensuing state of systemic hepatic insufficiency induces regenerative proliferation. A regulatory axis has been uncovered that is dependent on levels of circulating bile acids (BA), which are both synthesized and recycled by hepatocytes. BAs reclaimed from the gut enter the circulation and activate the farnesyl-X-receptor (FXR) in enterocytes (mice) or other cells (human). This induces secretion of FGF15/19 into the enterohepatic circulation [2-4]. At the liver, FGFR-signaling in hepatocytes feedback-regulates BA production by repressing CYP7A1 expression [5] and modulates bioenergetic pathways [6]. In a less-well understood process, BAs and FGF15/19 also coordinately regulate pro- and anti-regeneration activities in the liver. The balance of these activities determines whether the hepatocytes proliferate [7-9]. New insights: It is becoming increasingly recognized that redox signaling participates in many physiological functions. We recently reported that livers of mice in which hepatocytes lack both thioredoxin reductase-1 and glutathione reductase (TR/GR-null) - the entry points to the two major cytosolic antioxidant systems - are 2.1- fold larger than normal [10], suggesting these mice have a mis-calibrated hepatostat. These mice also have elevated BA levels. Surprisingly however, neither cholesterol-free diets nor inhibition of cholesterol synthesis to limit BA precursors, nor treatment with cholestyramine to increase fecal BA excretion, normalize circulating BAs. This suggests that, along with having a defective hepatostat in which pro-regeneration activities predominate, systemic feedback regulation of BA synthesis is disrupted in mice with TR/GR-null livers. What is proposed: Because the TR/GR-null condition is restricted to hepatocytes, we predict that FXR- induced production of FGF15 in enterocytes is normal. We hypothesize that hepatostat- and BA feedback- signals are redox-regulated and therefore disrupted in TR/GR-null hepatocytes. To test this hypothesis, we propose two specific aims:
Aim 1, to assess enterocytic FGF15 production and hepatocytic activity of FGF15- induced signaling cascades in WT or TR/GR-null livers.
Aim 2, to assess protein-Cys modifications on components of the FGFR4-dependent pathways in these livers and determine which of these affect signaling and gene expression outcomes that regulate the hepatostat. Anticipated outcomes and value: BAs function in lipid digestion, toxin-excretion, and the hepatostat. In turn, lipid catabolism, toxin exposure, and regeneration are each associated with increased oxidative stress. In this Exploratory Project, we hypothesize that there are previously unrecognized redox-regulated components on the BA/hepatostat axis that ensure appropriate coordination of these activities with the cellular redox status. Modulation of this could be helpful in therapies addressing liver injuries or toxic exposures.
Unlike most organs, mammalian liver is capable of full regeneration following loss of even the majority of its mass. Recent studies reveal components of the mechanism by which the liver `senses' its own size and, in response, coordinates regenerative growth to ensure a very precise liver:body mass-ratio. Our mouse models reveal a critical role for redox signaling in regulating liver size, which is investigated mechanistically here.
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