Inhibition of ceramide synthesis prevents diabetes, steatosis, and cardiovascular disease in rodents. Six different ceramide synthases (CerS) that differ in tissue distribution and substrate specificity account for the diversity in acyl-chain composition of distinct ceramide species. Haploinsufficiency for ceramide synthase 2 (CerS2), the dominant isoform in the liver that preferentially makes very-long-chain (C22/C24/C24:1) ceramides, led to compensatory increases in long-chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance. Mechanistic studies revealed that these metabolic effects were likely due to impaired β-oxidation resulting from inactivation of electron transport chain components. Inhibiting global ceramide synthesis negated the effects of CerS2 haploinsufficiency in vivo, and increasing C16-ceramides by overexpressing CerS6 recapitulated the phenotype in isolated, primary hepatocytes. Collectively, these studies reveal that altering sphingolipid acylation patterns impacts hepatic steatosis and insulin sensitivity and identify CerS6 as a possible therapeutic target for treating metabolic diseases associated with obesity.

Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates b-oxidation in hepatic cells and liver by an autophagy-lysosomal pathway. Furthermore, caffeine-induced autophagy involved down-regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high-fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. (HEPATOLOGY 2014;59:1366-1380 See Editorial on Page 1235 C affeine is one of the most widely consumed drugs in the world. Although its effect on whole-body metabolism and fat oxidation has been well documented in both animals and humans, [1][2][3] little is known about its direct action on the liver.The liver is the major site for fatty acid oxidation (FAO) in mammals. Decreased turnover of hepatic lipid droplets can lead to the development of fatty liver disease in humans. 4 Recently, the rapid rise in the prevalence of obesity and diabetes in the general population has contributed to a parallel increase in nonalcoholic fatty liver disease (NAFLD) in many parts of the world. Currently, it is estimated that up to 46% of the adult U.S. population may have hepatosteatosis. 5 Presently, there are no effective drug therapies for NAFLD, currently considered a risk factor for type II diabetes. 6 Recently, several studies have shown that caffeine intake in humans and animals is inversely correlated with severity of NAFLD and type II diabetes, 7-11 but the mechanism for this action is not known.

In the original publication of this article, the name of an author was inadvertently misspelled. The corrected author name is Bhagirath Chaurasia. The spelling is now correct in the online version of the article. The authors apologize for the inconvenience.

Background: Both ceramides and glucosylceramides have been implicated in the pathogenesis of insulin resistance. Results: These two classes of sphingolipids modulate insulin action but differ by both tissue specificity and mechanism of action. Conclusion: Ceramides and glucosylceramides are independent and separable antagonists of insulin signaling. Significance: These observations will contribute to our understanding of how sphingolipids contribute to obesity-related metabolic diseases.

ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach.