In der westlichen Überflussgesellschaft, die häufig von falschen Ernährungsgewohnheiten und mangelnder Bewegung geprägt ist, tritt die nicht alkoholinduzierte Fettlebererkrankung (NAFLD) immer häufiger als Diagnose in den Patientenakten auf, wobei deren Entstehung noch nicht im Detail charakterisiert ist. Sie betrifft in verschiedenen Schweregraden schätzungsweise 30% der Bevölkerung, wobei das initiale Stadium der geringgradigen Steatose noch reversibel ist und als benigne angesehen wird. Allgemein wird die Dysbalance zwischen Kalorienzufuhr und -Verbrauch, die zu einer positiven Energiebilanz führt, als die entscheidende Ursache für die Entstehung der NAFLD betrachtet. Jedoch ist bisher wenig über die konkreten molekularen Mechanismen bekannt, wobei auch der genaue Einfluss von nutritiven Faktoren, und deren Auswirkung auf den gesamten Lebermetabolismus weiterer Charakterisierung bedürfen.

A pronounced heterogeneity between hepatocytes in subcellular structure and enzyme activities was discovered more than 50years ago and initiated the idea of metabolic zonation. In the last decades zonation patterns of liver metabolism were extensively investigated for carbohydrate, nitrogen and lipid metabolism. The present review focuses on zonation patterns of the latter. We review recent findings regarding the zonation of fatty acid uptake and oxidation, ketogenesis, triglyceride synthesis and secretion, de novo lipogenesis, as well as bile acid and cholesterol metabolism. In doing so, we expose knowledge gaps and discuss contradictory experimental results, for example on the zonation pattern of fatty acid oxidation and de novo lipogenesis. Thus, possible rewarding directions of further research are identified. Furthermore, recent findings about the regulation of metabolic zonation are summarized, especially regarding the role of hormones, nerve innervation, morphogens, gender differences and the influence of the circadian clock. In the last part of the review, a short collection of models considering hepatic lipid metabolism is provided. We conclude that modeling, despite its proven benefit for understanding of hepatic carbohydrate and ammonia metabolisms, has so far been largely disregarded in the study of lipid metabolism; therefore some possible fields of modeling interest are presented.

The functional heterogeneity and plasticity of the liver parenchyma is known as metabolic zonation. Beside this the morphogen signaling takes a special position to control the homeostasis of metabolic zonation along the porto-central axis in the liver lobuli. Wnt factors are of particular importance, since the Wnt signaling has been identified as the main determinant of liver parenchyma zonation. For instance, the deletion of APC leads to an activation of the wnt signaling pathway in the pericentral area of the lobuli and thus resulting in a shift of the balance between anabolic and catabolic functions. However, little is known about the role of Wnt signaling in xenobiotic metabolism.

The Hedgehog signalling (HH-) pathway presents an evolutionary highly conserved cascade. Being one of the crucial modulators of embryogenesis and tissue differentiation its role in adult healthy organs like liver is often neglected. Interestingly, recent analyses identified the hedgehog signalling as a putative modulator of the circadian clock, which, at the molecular level, is organised by different self-regulatory transcriptional-translational feedback loops, comprising the so cold Core Clock Genes (CCGs). As an extensive biological process the clock is tightly linked to the elements of cell cycle control and intracellular signalling pathways, so the hedgehog-clock association seems to be reasonable. However, so far no data have been reported.

Entrained and reset by external cues, the internal circadian clock controls innate physiological processes, including liver metabolism. At the cellular level the circadian clock is characterised by a variety of core clock genes, which, acting as transcriptional factors, modulate the fluctuating expression of central metabolic genes [1]

Hintergrund: Der Hedgehog Signalweg (Hh) ist, ähnlich wie der Wnt/ß-Catenin Signalweg, für die Embryonalentwicklung und Gewebsdifferenzierung unabdingbar. Funktionen im adulten Gewebe, speziell in der Leber, konnten bis dato für das ß-Catenin-Signaling beim Stickstoff- und Glucosemetabolismus gezeigt werden (1,2). Da ein prinzipieller Zusammenhang zwischen dem Hh Signalweg und der circadianen Rhythmik bereits beschrieben ist (3), war es unser Ziel, den Einfluss dieser Kaskade auf die circadiane Rhythmik in adulten Hepatozyten zu untersuchen.