Fructose consumption has risen dramatically in recent decades due to use of sucrose and high fructose corn syrup in beverages and processed foods 1 , contributing to rising rates of obesity and non-alcoholic fatty liver disease (NAFLD) 2 – 4 . Fructose intake triggers hepatic de novo lipogenesis (DNL) 4 – 6 , which is initiated from acetyl-CoA. ATP-citrate lyase (ACLY) cleaves cytosolic citrate to generate acetyl-CoA and is upregulated upon carbohydrate consumption 7 . Ongoing clinical trials are pursuing ACLY inhibition for treatment of metabolic diseases 8 . Nevertheless, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unproven. Here we show, using in vivo isotope tracing, that liver-specific deletion of Acly fails to suppress fructose-induced DNL in mice. Dietary fructose is converted by the gut microbiome into acetate 9 , which supplies lipogenic acetyl-CoA independently of ACLY 10 . Depletion of the microbiome or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses conversion of a fructose bolus into hepatic acetyl-CoA and fatty acids, bypassing ACLY. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage and microbial acetate contribute to lipogenesis. The DNL transcriptional program, on the other hand, is activated in response to fructose in a manner independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism regulating hepatic DNL, in which fructolysis within hepatocytes provides a signal to promote DNL gene expression, while microbial acetate generation feeds lipogenic acetyl-CoA pools.

It is becoming clear that the manner by which the immune response resolves or contains infection by a pathogen varies according to the tissue that is affected. Unlike many peripheral cell types, CNS neurons are generally non-renewable. Thus, the cytolytic and inflammatory strategies that are effective in controlling infections in the periphery could be damaging if deployed in the CNS. Perhaps for this reason, the immune response to some CNS viral infections favours maintenance of neuronal integrity and non-neurolytic viral control. This modified immune response — when combined with the unique anatomy and physiology of the CNS — provides an ideal environment for the maintenance of viral genomes, including those of RNA viruses. Therefore, it is possible that such viruses can reactivate long after initial viral exposure, contributing to CNS disease.

Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. Significance: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer.

BACKGROUND: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. METHODS: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. RESULTS: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. CONCLUSION: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.