Metabolism is a fundamental process for all cellular functions. For decades, there has been growing evidence of a relationship between metabolism and malignant cell proliferation. Unlike normal differentiated cells, cancer cells have reprogrammed metabolism in order to fulfill their energy requirements. These cells display crucial modifications in many metabolic pathways, such as glycolysis and glutaminolysis, which include the tricarboxylic acid (TCA) cycle, the electron transport chain (ETC), and the pentose phosphate pathway (PPP) [1]. Since the discovery of the Warburg effect, it has been shown that the metabolism of cancer cells plays a critical role in cancer survival and growth. More recent research suggests that the involvement of glutamine in cancer metabolism is more significant than previously thought. Glutamine, a nonessential amino acid with both amine and amide functional groups, is the most abundant amino acid circulating in the bloodstream [2]. This chapter discusses the characteristic features of glutamine metabolism in cancers and the therapeutic options to target glutamine metabolism for cancer treatment.

Background & Aims: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood. Approach & Results: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced–ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1β release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1β release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1β production, and steatohepatitis in a murine model of AH. Conclusions: Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.

Massive inflammation and liver failure are main contributors to the high mortality in alcohol‐associated hepatitis (AH). In recent clinical trials, granulocyte colony‐stimulating factor (G‐CSF) therapy improved liver function and survival in patients with AH. However, the mechanisms of G‐CSF‐mediated beneficial effects in AH remain elusive. In this study, we evaluated effects of in vivo G‐CSF administration, using a mouse model of AH. G‐CSF treatment significantly reduced liver damage in alcohol‐fed mice even though it increased the numbers of liver‐infiltrating immune cells, including neutrophils and inflammatory monocytes. Moreover, G‐CSF promoted macrophage polarization toward an M2‐like phenotype and increased hepatocyte proliferation, which was indicated by an increased Ki67‐positive signal colocalized with hepatocyte nuclear factor 4 alpha (HNF‐4α) and cyclin D1 expression in hepatocytes. We found that G‐CSF increased G‐CSF receptor expression and resulted in reduced levels of phosphorylated β‐catenin in hepatocytes. In the presence of an additional pathogen‐associated molecule, lipopolysaccharide (LPS), which is significantly increased in the circulation and liver of patients with AH, the G‐CSF‐induced hepatoprotective effects were abolished in alcohol‐fed mice. We still observed increased Ki67‐positive signals in alcohol‐fed mice following G‐CSF treatment; however, Ki67 and HNF‐4α did not colocalize in LPS‐challenged mice. Conclusion: G‐CSF treatment increases immune cell populations, particularly neutrophil counts, and promotes M2‐like macrophage differentiation in the liver. More importantly, G‐CSF treatment reduces alcohol‐induced liver injury and promotes hepatocyte proliferation in alcohol‐fed mice. These data provide new insights into the understanding of mechanisms mediated by G‐CSF and its therapeutic effects in AH.