Hepatic triglyceride synthesis and nonalcoholic fatty liver disease

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease is a spectrum of diseases ranging from simple steatosis to cirrhosis. The hallmark of nonalcoholic fatty liver disease is hepatocyte accumulation of triglycerides. We will review the role of triglyceride synthesis in nonalcoholic fatty liver disease progression and summarize recent findings about triglyceride synthesis inhibition and prevention of progressive disease. RECENT FINDINGS: Attempts to inhibit triglyceride synthesis in animal models have resulted in improvement in hepatic steatosis. Studies in animal models of nonalcoholic fatty liver disease demonstrate that inhibition of acyl-coenzyme A:diacylglycerol acyltransferase, the enzyme that catalyzes the final step in triglyceride synthesis, results in improvement in hepatic steatosis and insulin sensitivity. We recently confirmed that hepatic specific inhibition of acyl-coenzyme A:diacylglycerol acyltransferase with antisense oligonucleotides improves hepatic steatosis in obese, diabetic mice but, unexpectedly, exacerbated injury and fibrosis in that model of progressive nonalcoholic fatty liver disease. When hepatocyte triglyceride synthesis was inhibited, free fatty acids accumulated in the liver, leading to induction of fatty acid oxidizing systems that increased hepatic oxidative stress and liver damage. These findings suggest that the ability to synthesize triglycerides may, in fact, be protective in obesity. SUMMARY: Nonalcoholic fatty liver disease is strongly associated with obesity and peripheral insulin resistance. Peripheral insulin resistance increases lipolysis in adipose depots, promoting increased free fatty acid delivery to the liver. In states of energy excess, such as obesity, the latter normally triggers hepatic triglyceride synthesis. When hepatic triglyceride synthesis is unable to accommodate increased hepatocyte free fatty acid accumulation, however, lipotoxicity results. Thus, rather than being hepatotoxic, liver triglyceride accumulation is actually hepato-protective in obese, insulin-resistant individuals.     

Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

Background

Multiple protein templates are commonly used in manual protein structure prediction. However, few automated algorithms of selecting and combining multiple templates are available.

Results

Here we develop an effective multi-template combination algorithm for protein comparative modeling. The algorithm selects templates according to the similarity significance of the alignments between template and target proteins. It combines the whole template-target alignments whose similarity significance score is close to that of the top template-target alignment within a threshold, whereas it only takes alignment fragments from a less similar template-target alignment that align with a sizable uncovered region of the target. We compare the algorithm with the traditional method of using a single top template on the 45 comparative modeling targets (i.e. easy template-based modeling targets) used in the seventh edition of Critical Assessment of Techniques for Protein Structure Prediction (CASP7). The multi-template combination algorithm improves the GDT-TS scores of predicted models by 6.8% on average. The statistical analysis shows that the improvement is significant (p-value < 10^-4). Compared with the ideal approach that always uses the best template, the multi-template approach yields only slightly better performance. During the CASP7 experiment, the preliminary implementation of the multi-template combination algorithm (FOLDpro) was ranked second among 67 servers in the category of high-accuracy structure prediction in terms of GDT-TS measure.

Conclusion

We have developed a novel multi-template algorithm to improve protein comparative modeling.     

Structure of ground‐dwelling ant communities in burned and unburned areas in Brazilian subtropical grasslands

Fire is frequently used in the management of pastures in southern Brazil, but its effects on ground‐dwelling ant communities in Brazilian subtropical grasslands is still poorly understood. Here, we compared ant species richness and composition between periodically burned and unburned areas in native grasslands of the Atlantic Forest biome. In total, we found 35 epigeic ant species in burned and unburned areas. There was slightly higher species richness in burned than in unburned areas, independent of the sampling period (season). There was a significant difference in richness over the sampling period (season effect). Species composition varied significantly between the areas, in which nine species (26%) occurred only in burned areas, eight (23%) occurred only in unburned areas, and 18 (51%) occurred in both. Four species showed a significant preference for burned sites (Camponotus crassus, Linepithema humile and two undetermined species of Pheidole and Solenopsis). Although this study did not separate fire effects on ground‐dwelling ant communities (due to sampling design), it provides new information regarding subtropical native grasslands that can be used as a baseline for future studies.     

Songbirds are resilient to hurricane disturbed habitats during spring migration

The Gulf of Mexico is a conspicuous feature of the Neotropical–Nearctic bird migration system. Traveling long distances across ecological barriers comes with considerable risks, and mortality associated with intercontinental migration may be substantial, including that caused by storms or other adverse weather events. However, little, if anything, is known about how migratory birds respond to disturbance‐induced changes in stopover habitat. Isolated, forested cheniere habitat along the northern coast of the Gulf of Mexico often concentrate migrants, during weather conditions unfavorable for northward movement or when birds are energetically stressed. We expected hurricane induced degradation of this habitat to negatively affect the abundance, propensity to stopover, and fueling trends of songbirds that stopover in coastal habitat. We used spring banding data collected in coastal Louisiana to compare migrant abundance and fueling trends before (1993–1996 and 1998–2005) and after hurricanes Rita (2006) and Ike (2009). We also characterized changes in vegetative structure before (1995) and after (2010) the hurricanes. The hurricanes caused dramatic changes to the vegetative structure, which likely decreased resources. Surprisingly, abundance, propensity to stopover, and fueling trends of most migrant species were not influenced by hurricane disturbance. Our results suggest that: 1) the function of chenieres as a refuge for migrants after completing a trans‐Gulf flight may not have changed despite significant changes to habitat and decreases in resource availability, and 2) that most migrants may be able to cope with habitat disturbance during stopover. The fact that migrants use disturbed habitat points to their conservation value along the northern coast of the Gulf of Mexico.     

Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.

Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.     

PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress

The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.     

Inverse relationship of epilithic algae and pelagic phosphorus in unproductive lakes: Roles of N2 fixers and light

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Evidence for epithelial-mesenchymal transitions in adult liver cells

Both myofibroblastic hepatic stellate cells (HSC) and hepatic epithelial progenitors accumulate in damaged livers. In some injured organs, the ability to distinguish between fibroblastic and epithelial cells is sometimes difficult because cells undergo epithelial-mesenchymal transitions (EMT). During EMT, cells coexpress epithelial and mesenchymal cell markers. To determine whether EMT occurs in adult liver cells, we analyzed the expression profile of primary HSC, two HSC lines, and hepatic epithelial progenitors. As expected, all HSC expressed HSC markers. Surprisingly, these markers were also expressed by epithelial progenitors. In addition, one HSC line expressed typical epithelial progenitor mRNAs, and these epithelial markers were inducible in the second HSC line. In normal and damaged livers, small ductular-type cells stained positive for an HSC marker. In conclusion, HSC and hepatic epithelial progenitors both coexpress epithelial and mesenchymal markers, providing evidence that EMT occurs in adult liver cells.