Lipid body accumulation alters calcium signaling dynamics in immune cells

There is well-established variability in the numbers of lipid bodies (LB) in macrophages, eosinophils, and neutrophils. Similarly to the steatosis observed in adipocytes and hepatocytes during hyperinsulinemia and nutrient overload, immune cell LB hyper-accumulate in response to bacterial and parasitic infection and inflammatory presentations. Recently we described that hyperinsulinemia, both in vitro and in vivo, drives steatosis and phenotypic changes in primary and transformed mast cells and basophils. LB reach high numbers in these steatotic cytosols, and here we propose that they could dramatically impact the transcytoplasmic signaling pathways. We compared calcium release and influx responses at the population and single cell level in normal and steatotic model mast cells. At the population level, all aspects of Fc?RI-dependent calcium mobilization, as well as activation of calcium-dependent downstream signaling targets such as NFATC1 phosphorylation are suppressed. At the single cell level, we demonstrate that LB are both sources and sinks of calcium following Fc?RI cross-linking. Unbiased analysis of the impact of the presence of LB on the rate of trans-cytoplasmic calcium signals suggest that LB enrichment accelerates calcium propagation, which may reflect a Bernoulli effect. LB abundance thus impacts this fundamental signaling pathway and its downstream targets.     

内质网应激与肝细胞脂类代谢

肝细胞担负大量的代谢功能,包括脂肪酸的合成与类固醇的代谢。内质网应激反应（ERstressresponse）作为内质网中特殊的机制用以保证内质网内部的稳态和功能正常。有研究指出内质网应激诱导的信号通路及其通路上的关键蛋白参与肝细胞的脂类代谢过程。本文主要讨论内质网应激反应影响肝细胞脂类代谢的机制,以及内质网应激与脂类代谢紊乱疾病的相关性。     

L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin

Nonalcoholic fatty liver disease is one of the most common liver diseases. L-tryptophan and its metabolite serotonin are involved in hepatic lipid metabolism and inflammation. However, it is unclear whether L-tryptophan promotes hepatic steatosis. To explore this issue, we examined the role of L-tryptophan in mouse hepatic steatosis by using a high fat and high fructose diet (HFHFD) model. L-tryptophan treatment in combination with an HFHFD exacerbated hepatic steatosis, expression of HNE-modified proteins, hydroxyproline content, and serum alanine aminotransaminase levels, whereas L-tryptophan alone did not result in these effects. We also found that L-tryptophan treatment increases serum serotonin levels. The introduction of adenoviral aromatic amino acid decarboxylase, which stimulates the serotonin synthesis from L-tryptophan, aggravated hepatic steatosis induced by the HFHFD. The fatty acid-induced accumulation of lipid was further increased by serotonin treatment in cultured hepatocytes. These results suggest that L-tryptophan increases the sensitivity to hepatic steatosis through serotonin production. Furthermore, L-tryptophan treatment, adenoviral AADC introduction, and serotonin treatment induced phosphorylation of the mammalian target of rapamycin (mTOR), and a potent mTOR inhibitor rapamycin attenuated hepatocyte lipid accumulation induced by fatty acid with serotonin. These results suggest the importance of mTOR activation for the exacerbation of hepatic steatosis. In conclusion, L-tryptophan exacerbates hepatic steatosis induced by HFHFD through serotonin-mediated activation of mTOR.     

High fat diet induced downregulation of microRNA-467b increased lipoprotein lipase in hepatic steatosis

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and is presently the most common chronic liver disease. However, the mechanisms underlying the development of steatosis remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a variety of biological functions. We have investigated the role of miRNA in the development of steatosis. We found that miR-467b expression is significantly downregulated in liver tissues of high-fat diet fed mice and in steatosis-induced hepatocytes. The downregulation of miR-467b resulted in the upregulation of hepatic lipoprotein lipase (LPL), the direct target of miR-467b. Moreover, the interaction between miR-467b and LPL was associated with insulin resistance, a major cause of NAFLD. These results suggest that downregulation of miR-467b is involved in the development of hepatic steatosis by modulating the expression of its target, LPL.     

Critical role of Kupffer cells in the management of diet-induced diabetes and obesity

The aim of this study was to investigate the role of Kupffer cell in glucose metabolism and hepatic insulin sensitivity in mice. Both phagocytic activity and secretory capacity of Kupffer cells were blunted 24 h after GdCl₃ administration. Glucose tolerance - evaluated following an oral glucose tolerance test (OGTT) - was higher in GdCl₃-treated mice whereas fasting insulinemia and HOMA-IR index decreased. The improvement of glucose tolerance and hepatic insulin signalling pathway after inhibition of Kupffer cells was supported by a lower hepatic gluconeogenic enzyme expression and a higher phosphorylation of Akt upon insulin challenge. Moreover, fasting hyperglycemia, insulin resistance and impaired glucose tolerance - induced by high fat (HF) diet - were improved through chronic administration of GdCl₃. Interestingly, the inhibition of Kupffer cell exerted antiobesity effects in HF-fed mice, and lowered hepatic steatosis. Therefore, strategies targeting Kupffer cell functions could be a promising approach to counteract obesity and related metabolic disorders.     

Dietary soy protein induces hepatic lipogenic enzyme gene expression while suppressing hepatosteatosis in obese female Zucker rats bearing DMBA-initiated mammary tumors

Fatty liver is associated with obesity and breast cancer. We used an obese rat model of mammary cancer to examine whether hepatosteatosis is modifiable by diet and associated with altered expression of hepatic lipogenic enzyme genes, thyroid hormone system genes and cholesterol metabolism-related genes. Beginning at the age of 5 weeks, lean and obese female Zucker rats were fed high-isoflavone soy protein- or casein (control protein)-containing diets. Rats were euthanized at 200 days of age [corresponding to 147 days after administration of carcinogen to induce mammary tumors; (Hakkak et al. in, Oncol Lett 2:29–36, 2011)]. Obese rats had a greater degree of liver steatosis than lean rats. Obese casein-fed rats had marked steatosis with small foci of mononuclear infiltration, whereas obese soy protein-fed rats had a significantly lower steatosis index. Comparisons between lean and obese casein-fed rats showed that obesity was associated with significant reductions in hepatic mRNA abundance for Glucose 6-Phosphate Dehydrogenase (G6PD), 6-Phosphogluconate Dehydrogenase (6PGD), Thyroid Receptor Alpha 1 (TRα1), Thyroid Receptor Beta 1 (TRβ1) and Iodothyronine Deiodinase 1 (DIO1). The soy protein diet was associated with increased expression of Fatty Acid Synthase (FASN), Malic Enzyme 1 (ME1), 6PGD, Sterol Regulatory Element Binding Protein-1c (SREBP-1c) and SREBP-2 genes in the livers of obese but not lean rats. Western blot analysis showed a significant induction of ME1 protein expression in the livers of obese, soy protein-fed rats, which paralleled the increased serum insulin level in this group. Long-term soy protein consumption can counter hepatic steatosis while coincidently promoting hepatic lipogenic gene expression, the latter likely a consequence of elevated serum insulin. We suggest that elevations in serum insulin, hepatic lipogenesis and cholesterol synthesis all contributed to the increased tumorigenesis previously observed for the obese, soy protein-fed rats.     

Lipid droplets and hepatitis C virus infection

Lipid droplets play an important part in the life cycle of hepatitis C virus and also are markers for steatosis, which is a common condition that arises during infection. These storage organelles are targeted by the viral core protein, which forms the capsid shell. Attachment of core to lipid droplets requires a C-terminal domain within the protein that is highly conserved between different virus isolates. In infected cells, the presence of core on lipid droplets creates loci that contain viral RNA and non-structural proteins involved in genome replication. Such locations may represent sites for initiating assembly and production of nascent virions. In addition to utilising lipid droplets as part the virus life cycle, hepatitis C virus induces their accumulation in infected hepatocytes. The mechanisms involved in this process are not understood but evidence from patient-based studies and model systems suggests the involvement of both viral and host factors.