The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray-based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin-deficient mice, the effects of leptin supplementation on liver regeneration in wildtype mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte-specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor. In conclusion, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration. (HEPATOLOGY 2004;40:1322-1332 T he liver regenerates in response to a variety of injuries. [1][2][3] The rodent partial hepatectomy model has been a useful tool with which to investigate the signals that regulate this regenerative response. Following partial hepatectomy, most of the remaining quiescent hepatocytes in the remnant liver tissue quickly proliferate leading to rapid restoration of appropriate liver mass. 4 Analyses of genetically and pharmacologically manipulated mice using this model have begun to identify the coordinated signaling events that regulate hepatic regeneration. These signals include activation of tumor necrosis factor ␣ (TNF␣) interleukin (IL)-6 signaling, 5-7 generation of mitochondrial reactive oxygen species 8 and prostaglandins 9 , and activation of stress-and mitogenactivated-protein kinase cascades. 10 These signals lead to activation of nuclear factor B (NF B) and other transcription factors, which direct an immediate early gene expression program culminating in growth factor-dependent hepatocellular reentry into and progression through the cell cycle [11][12][13] . Once t...

Summary Background In many differentiated cells microtubules are organized into polarized noncentrosomal arrays, yet few mechanisms that control these arrays have been identified. For example, mechanisms that maintain microtubule polarity in the face of constant remodeling by dynamic instability are not known. Drosophila neurons contain uniform polarity minus-end-out microtubules in dendrites, which are often highly branched. As undirected microtubule growth through dendrite branch points jeopardizes uniform microtubule polarity, we have used this system to understand how cells can maintain dynamic arrays of polarized microtubules. Results We find that growing microtubules navigate dendrite branch points by turning the same way, towards the cell body, 98% of the time, and that growing microtubules track along stable microtubules towards their plus ends. Using RNAi and genetic approaches, we show that kinesin-2, and the +TIPS EB1 and APC, are required for uniform dendrite microtubule polarity. Moreover, the protein-protein interactions and localization of Apc2-GFP and Apc-RFP to branch points suggests these proteins work together at dendrite branches. The functional importance of this polarity mechanism is demonstrated by the failure of neurons with reduced kinesin-2 to regenerate an axon from a dendrite. Conclusions We conclude that microtubule growth is directed at dendrite branch points, and that kinesin-2, APC and EB1 are likely to play a role in this process. We propose that is recruited to growing microtubules by +TIPS, and that the motor protein steers growing microtubules at branch points. This represents a newly discovered mechanism to maintain polarized arrays of microtubules.

The regenerative capability of liver is well known, and the mechanisms that regulate liver regeneration are extensively studied. Such analyses have defined general principles that govern the hepatic regenerative response and implicated specific extracellular and intracellular signals as regulated during and essential for normal liver regeneration. Nevertheless, the most proximal events that stimulate liver regeneration and the distal signals that terminate this process remain incompletely understood. Recent data suggest that the metabolic response to hepatic insufficiency might be the proximal signal that initiates regenerative hepatocellular proliferation. This review provides an overview of the data in support of a metabolic model of liver regeneration and reflects on the clinical implications and areas for further study suggested by these findings.

Liver disease in alpha-1-antitrypsin (␣1AT) deficiency is caused by a gain-of-toxic function mechanism engendered by the accumulation of a mutant glycoprotein in the endoplasmic reticulum (ER). The extraordinary degree of variation in phenotypical expression of this liver disease is believed to be determined by genetic modifiers and/or environmental factors that influence the intracellular disposal of the mutant glycoprotein or the signal transduction pathways that are activated. Recent investigations suggest that a specific repertoire of signaling pathways are involved, including the autophagic response, mitochondrial-and ER-caspase activation, and nuclear factor kappaB (NF B) activation. Whether activation of these signaling pathways, presumably to protect the cell, inadvertently contributes to liver injury or perhaps protects the cell from one injury and, in so doing, predisposes it to another type of injury, such as hepatocarcinogenesis, is not yet known. Recent studies also suggest that hepatocytes with marked accumulation of ␣1ATZ, globule-containing hepatocytes, engender a cancer-prone state by surviving with intrinsic damage and by chronically stimulating in 'trans' adjacent relatively undamaged hepatocytes that have a selective T he classic form of alpha-1-antitrypsin (␣1AT) deficiency, associated with homozygosity for the ␣1ATZ allele, is the most common genetic cause of liver disease in children. It also causes chronic liver injury and hepatocellular carcinoma in adults. 1 Moreover, the predilection for hepatocellular carcinoma in homozygotes for the Z allele is significantly greater than that attributable to cirrhosis alone. 1 The histopathological hallmark of the disease is intracellular globules in hepatocytes that stain positively with periodic acid-Schiff (PAS) after treatment with diastase, the so-called PAS-positive/ diastase-resistant globules. Early studies showed that these globules represent the mutant glycoprotein, ␣1ATZ, retained in the rough endoplasmic reticulum (ER) of liver cells (reviewed in Perlmutter 2 ). Although considerable discussion of these globules is found in the literature as well as investigation of their origin, relatively limited discussion, or investigation, has taken place, regarding the curious fact that many hepatocytes in these patients do not have globules (Fig. 1). Studies of the Z#2 mouse model, generated by using a human ␣1ATZ genomic fragment as transgene, 3 have shown that these globuledevoid cells occupy an increasing proportion of the liver as the animal ages and ultimately become the site of adenomas and carcinomas. 4 In more recent studies using the PiZ mouse model, another transgenic mouse created with a human ␣1ATZ genomic fragment, 5 we have shown that there is increased proliferation of these globule-devoid hepatocytes at a rate that is directly proportional to the number of globule-containing hepatocytes. 6

The regenerative capacity of the liver is well known, and the mechanisms that regulate this process have been extensively studied using experimental model systems including surgical resection and hepatotoxin exposure. The response to primary mitogens has also been used to investigate the regulation of hepatocellular proliferation. Such analyses have identified many specific cytokines and growth factors, intracellular signaling events, and transcription factors that are regulated during and necessary for normal liver regeneration. Nevertheless, the nature and identities of the most proximal events that initiate hepatic regeneration as well as those distal signals that terminate this process remain unknown. Here, we review the data implicating acute alterations in lipid metabolism as important determinants of experimental liver regeneration and propose a novel metabolic model of regeneration based on these data. We also discuss the association between chronic hepatic steatosis and impaired regeneration in animal models and humans and consider important areas for future research.