Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

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Highlights d Pyruvate carboxylase (PC) maintains hepatic TCA cycle function and gluconeogenesis d PC replenishes TCA cycle intermediates required for urea cycle and redox capacity d Loss of hepatic PC prevents hyperglycemia in obesity but worsens liver inflammation d PC moderates oxidative stress during obesity by maintaining NADPH and glutathione

Potthoff MJ, Potts A, He T, Duarte JA, Taussig R, Mangelsdorf DJ, Kliewer SA, Burgess SC. Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol 304: G371-G380, 2013. First published December 20, 2012; doi:10.1152/ajpgi.00400.2012.-Bile acid sequestrants are nonabsorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here, we demonstrate that the bile acid sequestrant, colesevelam, significantly reduced hepatic glucose production by suppressing hepatic glycogenolysis in diet-induced obese mice and that this was partially mediated by activation of the G protein-coupled bile acid receptor TGR5 and glucagon-like peptide-1 (GLP-1) release. A GLP-1 receptor antagonist blocked suppression of hepatic glycogenolysis and blunted but did not eliminate the effect of colesevelam on glycemia. The ability of colesevelam to induce GLP-1, lower glycemia, and spare hepatic glycogen content was compromised in mice lacking TGR5. In vitro assays revealed that bile acid activation of TGR5 initiates a prolonged cAMP signaling cascade and that this signaling was maintained even when the bile acid was complexed to colesevelam. Intestinal TGR5 was most abundantly expressed in the colon, and rectal administration of a colesevelam/bile acid complex was sufficient to induce portal GLP-1 concentration but did not activate the nuclear bile acid receptor farnesoid X receptor (FXR). The beneficial effects of colesevelam on cholesterol metabolism were mediated by FXR and were independent of TGR5/GLP-1. We conclude that colesevelam administration functions through a dual mechanism, which includes TGR5/GLP-1-dependent suppression of hepatic glycogenolysis and FXR-dependent cholesterol reduction. bile acids; glucagon-like peptide-1; TGR5; diabetes-induced obesity; FGF-15; FXR BILE ACID SEQUESTRANTS ARE orally administered nonabsorbable resins designed to treat hypercholesterolemia (23) but that have unexpected beneficial effects on glycemia in subjects with type 2 diabetes mellitus (T2DM) (17). This observation has been confirmed in multiple human studies, animal models, and with a variety of different bile acid binding resins (reviewed in Ref. 41). Colesevelam is a bile acid sequestrant used to treat T2DM, but the mechanisms by which it and other sequestrants act on glucose metabolism are incompletely understood. Inasmuch as colesevelam passes through the digestive track unaltered, its efficacy on both cholesterol and glucose metabolism are thought to originate from its high bile acid-binding affinity.Bile acids are amphipathic molecules synthesized in liver, stored in the gallbladder, and secreted into the small intestine to facilitate dietary lipid absorption (48). Ileal bile acid reabsorption and uptake by the liver is nearly q...