The effects of glucose and lipids in steatotic and non-steatotic livers in conditions of partial hepatectomy under ischaemia-reperfusion.

BACKGROUND: Steatosis is a risk factor in partial hepatectomy (PH) under ischaemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. Nutritional support strategies, as well as the role of peripheral adipose tissue as energy source for liver regeneration, remain poorly investigated. AIMS: To investigate whether the administration of either glucose or a lipid emulsion could protect steatotic and non-steatotic livers against damage and regenerative failure in an experimental model of PH under I/R. The relevance of peripheral adipose tissue in liver regeneration following surgery is studied. METHODS: Steatotic and non-steatotic rat livers were subjected to surgery and the effects of either glucose or lipid treatment on damage and regeneration, and part of the underlying mechanisms, were investigated. RESULTS: In non-steatotic livers, treatment with lipids or glucose provided the same protection against damage, regeneration failure and ATP drop. Adipose tissue was not required to regenerate non-steatotic livers. In the presence of hepatic steatosis, lipid treatment, but not glucose, protected against damage and regenerative failure by induction of cell cycle, maintenance of ATP levels and elevation of sphingosine-1-phosphate/ceramide ratio and phospholipid levels. Peripheral adipose tissue was required for regenerating the steatotic liver but it was not used as an energy source. CONCLUSION: Lipid treatment in non-steatotic livers provides the same protection as that afforded by glucose in conditions of PH under I/R, whereas the treatment with lipids is preferable to reduce the injurious effects of liver surgery in the presence of steatosis.

Resistin and visfatin in steatotic and non-steatotic livers in the setting of partial hepatectomy under ischemia-reperfusion.

BACKGROUND & AIMS: This study examined whether the regulation of resistin and visfatin could reduce damage and improve regeneration in both steatotic and non-steatotic livers undergoing partial hepatectomy under ischemia-reperfusion, a procedure commonly applied in clinical practice to reduce bleeding. METHODS: Resistin and visfatin were pharmacologically modulated in lean and obese animals undergoing partial hepatectomy under ischemia-reperfusion. RESULTS: No evident role for these adipocytokines was observed in non-steatotic livers. However, obese animals undergoing liver surgery showed increased resistin in liver and plasma, without changes in adipose tissue, together with visfatin downregulation in liver and increment in plasma and adipose tissue. Endogenous resistin maintains low levels of visfatin in the liver by blocking its hepatic uptake from the circulation, thus regulating the visfatin detrimental effects on hepatic damage and regenerative failure. Indeed, the administration of anti-resistin antibodies increased hepatic accumulation of adipocyte-derived visfatin, exacerbating damage and regenerative failure. Interestingly, treatment with anti-visfatin antibodies protected steatotic livers, and similar results were obtained with the concomitant inhibition of resistin and visfatin. Thus, when visfatin was inhibited, the injurious effects of anti-resistin antibodies disappeared. Herein we show that upregulation of visfatin increased NAD levels in the remnant steatotic liver, whereas visfatin inhibition decreased them. These later observations suggest that visfatin may favour synthesis of NAD instead of DNA and induces alterations in amino acid metabolism-urea cycle and NO production, overall negatively affecting liver viability. CONCLUSIONS: Our results indicate the clinical potential of visfatin blocking-based therapies in steatotic livers undergoing partial hepatectomy with ischemia-reperfusion.

Adiponectin and resistin protect steatotic livers undergoing transplantation.

BACKGROUND & AIMS: Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion. Controversial roles for adiponectin and related adipocytokines visfatin and resistin have been described in different liver pathologies, nevertheless it is unknown their possible implication in ischemia-reperfusion injury associated with liver transplantation. Our study aimed at characterizing the role of the adiponectin-derived molecular pathway in transplantation with steatotic and non-steatotic liver grafts. METHODS: Steatotic and non-steatotic liver transplantation was carried out and the hepatic levels of adiponectin, visfatin and resistin were measured and modulated either pharmacologically or surgically. RESULTS: Steatotic liver grafts exhibited downregulation of both adiponectin and resistin when subjected to transplantation. Adiponectin pre-treatment only protected steatotic grafts and did it so through a visfatin-independent and resistin-dependent mechanism. Adiponectin-derived resistin accumulation activated the PI3K/Akt pathway, unravelling AMPK as an upstream mediator of adiponectin's actions in steatotic grafts. Strategies aimed at increasing adiponectin including either AMPK activators or the induction of ischemic preconditioning (which activates AMPK) increased resistin accumulation, prevented the downregulation of PI3K/Akt pathway and protected steatotic liver grafts. Conversely, PI3K/Akt pathway upregulation and hepatic protection induced by adiponectin were abolished when resistin action was inhibited. CONCLUSIONS: Our findings reveal a new protective pathway in steatotic liver transplantation, namely AMPK-adiponectin-resistin-PI3K/Akt, which may help develop new strategies aimed at increasing either adiponectin or resistin in the steatotic liver undergoing transplant to ultimately increase organ donor pool and reduce waiting list.

Retinol binding protein 4 and retinol in steatotic and nonsteatotic rat livers in the setting of partial hepatectomy under ischemia/reperfusion.

Steatotic livers show increased hepatic damage and impaired regeneration after partial hepatectomy (PH) under ischemia/reperfusion (I/R), which is commonly applied in clinical practice to reduce bleeding. The known function of retinol-binding protein 4 (RBP4) is to transport retinol in the circulation. We examined whether modulating RBP4 and/or retinol could protect steatotic and nonsteatotic livers in the setting of PH under I/R. Steatotic and nonsteatotic livers from Zucker rats were subjected to PH (70%) with 60 minutes of ischemia. RBP4 and retinol levels were measured and altered pharmacologically, and their effects on hepatic damage and regeneration were studied after reperfusion. Decreased RBP4 levels were observed in both liver types, whereas retinol levels were reduced only in steatotic livers. RBP4 administration exacerbated the negative consequences of liver surgery with respect to damage and liver regeneration in both liver types. RBP4 affected the mobilization of retinol from steatotic livers, and this revealed actions of RBP4 independent of simple retinol transport. The injurious effects of RBP4 were not due to changes in retinol levels. Treatment with retinol was effective only for steatotic livers. Indeed, retinol increased hepatic injury and impaired liver regeneration in nonsteatotic livers. In steatotic livers, retinol reduced damage and improved regeneration after surgery. These benefits of retinol were associated with a reduced accumulation of hepatocellular fat. Thus, strategies based on modulating RBP4 could be ineffective and possibly even harmful in both liver types in the setting of PH under I/R. In terms of clinical applications, a retinol pretreatment might open new avenues for liver surgery that specifically benefit the steatotic liver.

Does adiponectin benefit steatotic liver transplantation?

Strategies for improving the viability of steatotic donor livers could increase the number of organs suitable for transplantation. There is evidence that adiponectin, the most abundant adipose-specific adipokine, acts as an anti-obesity and anti-inflammatory hormone. Here we review the signaling pathways of adiponectin and the possible therapies based on adiponectin regulation that have been examined or applied clinically. Recent studies on the role of adiponectin in steatotic livers subjected to ischemia/reperfusion are discussed. The data suggest that further investigations are required to determine whether adiponectin is a potential therapeutic target in liver transplantation.

Cyclic adenosine 3',5'-monophosphate in rat steatotic liver transplantation.

Numerous steatotic livers are discarded as unsuitable for transplantation (TR) because of their poor tolerance of ischemia/reperfusion (I/R). Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents protect against I/R injury both in nonsteatotic livers that have been removed from non-heart-beating donors and subjected to warm ischemia or cold ischemia (CIS) and in perfused, isolated livers. Ischemic preconditioning (PC), which is based on brief periods of I/R, protects steatotic liver grafts, but the mechanism that is responsible is poorly understood. This study examines the role of cAMP in the vulnerability shown by steatotic livers to TR-associated I/R injury and the benefits of PC in this situation. Steatotic livers with or without PC were transplanted into Zucker rats. The hepatic levels of cAMP were measured and altered pharmacologically. Our results indicate that the cAMP levels in the nonsteatotic liver grafts were similar to those found in a sham group. However, high cAMP levels were observed in steatotic liver grafts. The blockage of cAMP generation by adenylate cyclase inhibitor pre-treatment or PC had the following results: reduced hepatic injury and increased survival of steatotic graft recipients; greater preservation of adenosine triphosphate (ATP) and reduced lactate accumulation throughout CI. This blockade of cAMP by a nitric oxide-dependent mechanism protected steatotic liver grafts against oxidative stress and microvascular disorders after reperfusion. In conclusion, cAMP blocking-based strategies could protect patients against the inherent risk of steatotic liver failure after TR.