Background/Aims: Nonalcoholic fatty liver disease (NAFLD) is the worldwide most common liver disease and therefore frequently observed in patients undergoing hepatic surgery.Etiologically NAFLD relates to insulin resistance and can progress to fibro-inflammatory nonalcoholic steatohepatitis (NASH).This study investigated associations of hepatic mRNA and preoperative serum levels of the Nicotinamide-phosphoribosyltransferase (NAMPT) visfatin with NAFLD histology, markers of insulin resistance, inflammation and postoperative liver recovery.Methods: NAFLD histology was evaluated in 44 subjects undergoing liver surgery.Fasting blood samples and liver biopsies were harvested.Clinical chemistry and homeostasis model of insulin resistance (HOMA-IR) were evaluated.Circulating visfatin/NAMPT was measured by enzyme linked-immunosorbent assay, mRNA by RT-PCR.Postoperative liver recovery was studied in a subset of subjects using the LiMAx-method.Results: Visfatin/NAMPT mRNA and serum levels showed no associations with hepatic steatosis, fibro-inflammation, ballooning degeneration or insulin resistance (P > 0.05, resp.).Circulating visfatin/NAMPT correlated with ferritine (r = 0.325; P = 0.032) and serum iron (r = -0.342;P = 0.023) as surrogates of hepatic oxidative stress, liver mRNA with white blood cell count (r = 0.357; P = 0.062) and hepatic CRP mRNA (r = 0.346; P = 0.061).Moreover, circulating visfatin/NAMPT was related to mean postoperative LiMAx liver recovery (r = 0.480; P = 0.044) and subjects reaching physiological liver function capacity within ten days after surgery had elevated preoperative serum visfatin/NAMPT (P = 0.014). Conclusions:Visfatin/NAMPT is related to markers of oxidative stress, inflammation and liver recovery after hepatic surgery, but not to NAFLD histology or insulin resistance.

The liver integrates multiple metabolic pathways to warrant systemic energy homeostasis. An excessive lipogenic flux due to chronic dietary stimulation contributes to the development of hepatic steatosis, dyslipidemia and hyperglycemia. Here we show that the oxidoreductase retinol saturase (RetSat) is involved in the development of fatty liver. Hepatic RetSat expression correlates with steatosis and serum triglycerides (TGs) in humans. Liver-specific depletion of RetSat in dietary obese mice lowers hepatic and circulating TGs and normalizes hyperglycemia. Mechanistically, RetSat depletion reduces the activity of carbohydrate response element binding protein (ChREBP), a cellular hexose-phosphate sensor and inducer of lipogenesis. Defects upon RetSat depletion are rescued by ectopic expression of ChREBP but not by its putative enzymatic product 13,14-dihydroretinol, suggesting that RetSat affects hepatic glucose sensing independent of retinol conversion. Thus, RetSat is a critical regulator of liver metabolism functioning upstream of ChREBP. Pharmacological inhibition of liver RetSat may represent a therapeutic approach for steatosis.

Problemstellung: Im Kontext der humanen nicht-alkoholischen Fettlebererkrankung (NAFLD) gelten entzündliche hepatische Prozesse als mit der Adipositas assoziiert. Eine verknüpfende Rolle spielen dabei von Fettzellen sezernierte Mediatoren, sogenannte Adipozytokine. Dies wurde auch für Chemerin postuliert, ein in jüngerer Zeit identifiziertes Adipozytokin mit chemotaktischer Wirkung auf bestimmte Populationen inflammatorischer Zellen. Erhöhte Serumspiegel von Chemerin in der Vena hepatica leberzirrhotischer Patienten deuten daneben auf eine zusätzliche Expression des Adipozytokins in der Leber hin. Dies wurde für den Menschen bisher allerdings nicht belegt. Gegenstand dieser Studie war daher die Untersuchung der hepatischen Genexpression von Chemerin und dessen Rezeptor CMKLR1 bei Patienten mit histopathologisch nachgewiesener NAFLD im Vergleich zu Kontrollpatienten ohne NAFLD.

Objective: Inflammatory states of non-alcoholic fatty liver disease (NAFLD) are associated with obesity via adipocytokines. Circulating levels of the adipocytokine chemerin are in vivo associated with NAFLD and hepatic cirrhosis. However, hepatic gene transcription of chemerin and its receptor CMKLR1 are rarely studied, especially in human NAFLD.

Fragestellung: Die AMPK, ein ubiquitärer zellulärer Energiesensor und das Ziel der Metformintherapie, spielt im Leberstoffwechsel eine zentrale Rolle und reguliert u.a. die Glukoseproduktion und die de novo Lipogenese. In Tiermodellen ist für NAFLD und Diabetes mellitus Typ 2 (DMT2) eine reduzierte Phosphorylierung an Thr172 der katalytischen α Untereinheit der AMPK und eine daraus resultierende Aktivitätsminderung ohne Veränderung der Gesamtproteinmenge gezeigt. Adiponektin gilt als Aktivator der AMPK und vermittelt seine Wirkung zellulär durch die Rezeptoren AdipoR1 und R2. Der Zusammenhang zwischen AMPK und Adiponektin in der humanen NAFLD±DMT2 stand im Fokus dieser Untersuchung.