It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, β-oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling - including the vitamin D receptor and the liver receptor homolog 1 - in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer.

Objective Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-β signalling, VD has been proposed as an antifibrotic treatment. Design We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD. Results Treating phHSC with VD ameliorated TGF-β-induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele. Conclusions VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.

Als zentrales Stoffwechselorgan nimmt die Leber eine Schlüsselrolle bei der Metabolisierung hochkalorischer, insbesondere fettreicher Ernährung ein. Im Zusammenspiel mit dem Gastrointestinaltrakt, dem Fett- und Muskelgewebe und anderen Organsystemen ist die Leber entscheidend am Fettmetabolismus beteiligt. Durch Aktivierung von Transkriptionsfaktoren wie dem „carbohydrate responsive element binding protein (ChREBP)”, „sterol response element binding protein-1c (SREBP-1c)” oder der „forkhead box 01 (Fox01)” wird die Fettsäuresynthese gesteigert. Die Translokation von freien Fettsäuren wird über bestimmte Fetttransportproteine wie dem „fatty acid transport proteins (FATP)”, der „fatty acid translocase (FAT/CD36)”, Caveolin-1 und dem „fatty acid binding protein (FABP)” vermittelt. Bei Störungen des Fettmetabolismus oder bei übermäßigem Fettangebot kommt es häufig zu Fettablagerungen in Form von Lipidtröpfchen innerhalb der Hepatozyten (nichtalkoholische Fettlebererkrankung; alkoholische Steatohepatitis, akute Schwangerschaftsfettleber, Hepatitis C). Neuere Daten belegen interessanterweise, dass die Fettablagerung in den Hepatozyten für die Leberregenration essenziell ist. Hieraus ergibt sich zunehmend die Erkenntnis, dass die Steatosis nicht ausschließlich das Resultat einer Stoffwechselstörung ist. Vielmehr scheinen bereits kleinste Veränderungen in der β-Oxidation, bei Transportproteinen und/oder den Signalwegen eine Steatosis zu bedingen und das Fortschreiten der o. a. Lebererkrankungen voranzutreiben. Durch neue experimentelle Erkenntnisse über die Mechanismen der Leberverfettung ergeben sich potenzielle neue therapeutische Optionen. As a key metabolic organ, the liver is central to the imbalance of high-caloric diets, and particularly dietary fat consumption, in the industrialized countries and their association with the increasing prevalence of morbid obesity. By interacting with the intestinal tract and adipose tissue, the liver plays a key role in various aspects of lipid metabolism. Increasing activation of transcription factors, such as carbohydrate responsive element binding protein (ChREBP), sterol response element binding protein-1c (SREBP-1c), or forkhead box 01 (Fox01), may contribute to fatty acid synthesis. Their translocation occurs via fatty acid transporters such as fatty acid transport proteins (FATP), fatty acid translocase (FAT/CD36), caveolin-1 and fatty acid binding protein (FABP). Eventually, the accumulation of fat in the form of lipid droplets within the hepatocytes results in hepatic steatosis which, indeed, is a hallmark of liver diseases such as non-alcoholic fatty liver disease, alcoholic fatty liver, acute fatty liver in pregnancy, and hepatitis C. In contrast, lipid accumulation within hepatocytes during liver regeneration is essential. It is thus now becoming clear that steatosis is not only a mere consequence of metabolic imbalance, but that it is also a result of discrete alterations in the β-oxidation, transport mechanisms, and signaling pathways involved in the synthesis, systemic traffic modalities, and cellular effects of fatty acids. Such a novel insight offers potential options for improved treatment.