Adipose to the rescue: Peripheral fat fuels liver regeneration
Authors: Sundararajah Thevananther
Journal: Hepatology (2010)

Characterization of key cellular and molecular mechanisms responsible for efficient liver regeneration in response to acute loss of liver mass has been an active area of investigation for the past several decades.1 The intriguing search for the molecular identity of one or more factors responsible for liver regeneration has contributed substantially to our current knowledge of the functional significance of key humoral factors and temporal events necessary for efficient liver regeneration. Several early events associated with liver regeneration have been attributed to acute hemodynamic changes and associated shear-stress–induced release of humoral factors such as nucleotides and nitric oxide from the hepatic parenchyma.2-6 Cytokine-mediated and growth factor–mediated induction of cell signaling has been shown to be integral to the activation of a highly orchestrated gene expression program responsible for the stepwise reorganization of extracellular matrix, cell proliferation, and liver growth.1 fld, fatty liver dystrophy. Studies based on 70% partial hepatectomy of rodents, especially in gene knockout and transgenic mice, have uncovered the functional significance of distinct signaling cascades and genes necessary for cell proliferation and survival in regenerating livers. However, despite distinct delays and profound impairments in hepatocyte proliferation seen in most experimental models, liver growth continues until the optimal ratio of liver weight to body weight—a species-specific set point—is reached. Nevertheless, findings from these studies have led to the current consensus that liver regeneration is a complex multifactorial process mediated via the activation of multiple and redundant pathways in healthy livers.1 Enthusiasm for further characterization of functional significance of new genes and cell signaling pathways remains high because of the potential for finding novel therapies to stimulate liver regeneration in acute and chronic liver diseases that negatively impact liver regeneration. The report by Gazit et al. in this issue of Hepatology offers new insights into mechanisms of liver regeneration focusing on the contribution of peripheral lipid stores and systemic lipolysis in the liver's ability to regenerate in response to 70% partial hepatectomy.7 The present study was prompted by previous observations that partial hepatectomy induces transient hypoglycemia followed by lipid accumulation within hepatocytes that precedes the time of peak hepatocyte proliferation in mice. The authors previously reported that pharmacologic and genetic interventions that suppress the early induction of transient hypoglycemia and hepatic steatosis are able to inhibit liver regeneration in mice.8-10 They reason that the early induction of hypoglycemia may be a potential trigger for the release of fatty acids from peripheral lipid stores and that fatty acids derived from peripheral adipose tissues, in turn, may be responsible for transient lipid accumulation within hepatocytes in regenerating livers (Fig. 1). To test their hypothesis that catabolism of systemic adipose stores are essential for liver regeneration, the authors performed 70% partial hepatectomy on fatty liver dystrophy (fld) mice, which exhibit partial lipodystrophy and have diminished peripheral adipose stores. Supporting their hypothesis, fld mice exhibited attenuated development of hypoglycemia, hepatic lipid accumulation, and impaired hepatocyte proliferation in response to 70% partial hepatectomy.7 They conclude that hepatic insufficiency is the primary trigger for the induction of a systemic catabolic response based on their observation in two independent experimental models, partial hepatectomy, and carbon tetrachloride–mediated injury in mice. Liver regeneration is dependent on systemic catabolic response from peripheral adipose stores. Partial hepatectomy and loss of liver mass (and function) lead to hepatic insufficiency and systemic hypoglycemia, which is a potential trigger for lipolysis and fatty acid release from peripheral adipose stores. Fatty acid uptake by the remnant liver results in transient hepatic steatosis, essential for effective liver regeneration. Data presented in this study supports the notion that catabolism of total body and fat mass after partial hepatectomy occurs in proportion to the degree of induced hepatic insufficiency. However, the decline in lean mass did not correlate with the extent of hepatic insufficiency induced after one-third versus two-thirds partial hepatectomy.7 These findings provide direction for future studies to address key questions pertaining to liver:body mass regulation and identification of relevant body mass compartments that impact growth responses in the liver. Maintenance of metabolic homeostasis by balancing extrahepatic energy consumption with dietary nutrient uptake is one of the essential functions of the liver.11 Remarkably, regenerating livers manage to execute a robust program supporting liver regrowth and organogenesis, while maintaining adequate liver-specific metabolic, synthetic, and detoxification functions essential for the viability of the organism. The current studies by Gazit et al. that implicate systemic catabolic response as an essential mediator of liver regeneration provide intriguing new insight into the complex interplay of metabolism and growth regulation in regenerating livers.7 These new findings have substantial clinical implications, especially with regard to dextrose administration to patients who have undergone partial hepatic resection. Early studies in rats report paradoxical effects of glucose feeding on liver regeneration and survival after partial hepatectomy.12 Glucose feeding corrected life-threatening hypoglycemia following 90% hepatectomy. However, prophylactic glucose administration after 68% hepatectomy attenuated the regenerative response in rats. Although glucose administration is essential in preventing lethal hypoglycemia, the data presented in the study by Gazit et al. highlight the need to evaluate the potential implications of dextrose administration in patients subjected to partial hepatic resections. Although early induction of hypoglycemia can potentially trigger a systemic catabolic response, peripheral fatty acid release, and lipid accumulation within hepatocytes, the importance of transient hepatic steatosis for efficient liver regeneration has been questioned.13 Recent work by Newberry et al. examined the importance of hepatic steatosis for efficient liver regeneration in several murine models of altered hepatic lipid metabolism (liver fatty acid binding protein knockout [L-Fabp−/−]; intestine-specific microsomal triglyceride transfer protein knockout [MTP-IKO]; peroxisome proliferator activated receptor-α knockout [PPARα−/−]; liver-specific fatty acid synthase knockout [FAS-KOL]) and failed to observe a clear correlation between hepatic triglyceride content and liver regeneration.13 Interestingly, hepatic triglyceride content increased in response to partial hepatectomy in each of the aforementioned genetic models, but to a lesser extent than in controls, leading to the suggestion by Newberry et al. of a role for a potential "threshold of adaptive lipogenesis", which is not influenced by respective gene loss in the aforementioned knockout mouse models. These interesting observations clearly highlight the need for in-depth analysis of mechanisms of transient induction of hepatic steatosis in regenerating livers and its role in liver regeneration. In summary, the current report by Gazit et al. highlights the significance of systemic catabolic response in regenerating livers and the importance of fatty acids released from peripheral lipid stores as major mediators of transient hepatic steatosis, which is necessary for efficient liver regeneration in mice. These findings provide novel insights into our understanding of metabolic control of liver regeneration with implications in the management of patients undergoing hepatic resections.