The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis

: Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms’ metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma.

A novel model for ex situ reperfusion of the human liver following subnormothermic machine perfusion

Machine perfusion-based organ preservation techniques are prudently transitioning into clinical practice. Although experimental data is compelling, the outcomes in the highly variable clinical donation-transplantation setting are unpredictable. Here, we offer an intermediate tool for pre-clinical assessment of human donor livers. We present a model for ex situ reperfusion of discarded human livers and report on its application in three human livers that have undergone subnormothermic (21[Formula: see text]C) machine perfusion as an experimental preservation method. During reperfusion, the livers macroscopically reperfused in the first 15 minutes, and remained visually well-perfused for 3 hours of ex situ reperfusion. Bile production and oxygen consumption were observed throughout ex situ reperfusion. ATP levels increased 4.25-fold during SNMP. Between the end of SNMP and the end of reperfusion ATP levels dropped 45%. ALT levels in blood increased rapidly in the first 30 minutes and ALT release continued to taper off towards the end of perfusion. Release of CRP, TNF-[Formula: see text], IL-1[Formula: see text], and IL-12, IFN-[Formula: see text] was sustained during reperfusion. These findings support the use of this model for the evaluation of novel human liver preservation techniques.

Liver radiofrequency ablation compromises the biological gut barrier

Aim: Liver radiofrequency ablation (RFA) has been shown to disrupt the mechanical component of the gut barrier. The aim of the present study was to investigate the consequences of liver RFA on the biological gut barrier in terms of the effects of bile production rate and bowel inflammatory state on intestinal microflora balance. Method: A total of 25 New Zealand rabbits were assigned to five groups ( n = 5 per group): group CBD: subjected to common bile duct (CBD) extracorporeal bypass; group CBD-RFA: subjected to CBD bypass plus one session of open liver RFA; group RFA: subjected to liver RFA; group sham: subjected to sham operation; and group TBD: subjected to total bile deviation (TBD). In groups CBD and CBD-RFA, bile production rate was assessed for 48 h. In groups sham and RFA, measurement of biliary glycine conjugates of cholic and deoxycholic acid levels, histopathologic examination of the non-ablated liver tissue, morphometric analysis, and histopathologic examination of the terminal ileum and microbiological analysis of fecal and tissue samples collected from the jejunum and the cecum (and in group TBD) were performed at 48 h post-operation. Results: One session of liver RFA resulted in ablation of 18.7 ± 2.7% of liver weight. Following liver RFA, bile production rate was reduced, while the levels of biliary bile salts were not affected. There was mild injury of the non-ablated liver parenchyma, mild intestinal wall inflammation, intestinal mucosa atrophy, and intestinal microbial population overgrowth. Conclusion: Reduced in bile production and mild bowel inflammation secondary to liver RFA impaired the biological gut barrier as manifested by intestinal microflora imbalance.

Effects of essential fatty acid deficiency on enterohepatic circulation of bile salts in mice

Essential fatty acid (EFA) deficiency in mice has been associated with increased bile production, which is mainly determined by the enterohepatic circulation (EHC) of bile salts. To establish the mechanism underlying the increased bile production, we characterized in detail the EHC of bile salts in EFA-deficient mice using stable isotope technique, without interrupting the normal EHC. Farnesoid X receptor (FXR) has been proposed as an important regulator of bile salt synthesis and homeostasis. In Fxr −/− mice we additionally investigated to what extent alterations in bile production during EFA deficiency were FXR dependent. Furthermore, we tested in differentiating Caco-2 cells the effects of EFA deficiency on expression of FXR-target genes relevant for feedback regulation of bile salt synthesis. EFA deficiency-enhanced bile flow and biliary bile salt secretion were associated with elevated bile salt pool size and synthesis rate (+146 and +42%, respectively, P < 0.05), despite increased ileal bile salt reabsorption (+228%, P < 0.05). Cyp7a1 mRNA expression was unaffected in EFA-deficient mice. However, ileal mRNA expression of Fgf15 (inhibitor of bile salt synthesis) was significantly reduced, in agreement with absent inhibition of the hepatic bile salt synthesis. Bile flow and biliary secretion were enhanced to the same extent in EFA-deficient wild-type and Fxr −/− mice, indicating contribution of other factors besides FXR in regulation of EHC during EFA deficiency. In vitro experiments show reduced induction of mRNA expression of relevant genes upon chenodeoxycholic acid and a selective FXR agonist GW4064 stimulation in EFA-deficient Caco-2 cells. In conclusion, our data indicate that EFA deficiency is associated with interrupted negative feedback of bile salt synthesis, possibly because of reduced ileal Fgf15 expression.

Correction of hepatobiliary pathology by the complex herbal remedy

The influence of complex herbal remedy on the secretary and metabolic functions of a liver was investigated in rates with experimental toxic hepatitis and hypercholesterolemia. The result obtained have shown that complex herbal remedy shortened the time of evolution and decreased hepatic enzymes (AST, ALT, and GGT), alkaline phosphates, total bilirubin, and cholesterol. It has also been shown that complex herbal remedy increased the protein synthesis of hepatocyte and hampered lipolysis processes. On the other hand, the active components of this remedy regulated the excessive bile production. During complex herbal remedy administration, the rheologycal properties of bile are normalized, bile acid pool extends, and total cholesterol in bile reduces. Along with hepatoprotective properties, remedy has the expressive choleretic and cholekinetic effects.