Purpose Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.
PPARα (PPARA), expressed in most oxidative tissues, is a major regulator of lipid homeostasis; hepatic PPARA plays a critical role during the adaptive fasting response by promoting FA oxidation (FAO). To clarify whether extrahepatic PPARA activity can protect against lipid overload when hepatic PPARA is impaired, lipid accumulation was compared in WT ( ), total body-null ( ), and hepatocyte-specific-null ( ) mice that were fasted for 24 h. Histologic staining indicated reduced lipid accumulation in versus mice, and biochemical analyses revealed diminished medium- and long-chain FA accumulation in mouse livers. Hepatic PPARA target genes were suppressed in both mouse models. Serum FFAs increased in all genotypes after fasting but were highest in mice. In mice, FAO genes were increased in brown adipose tissue, heart, and muscle, and total lipase activity was elevated in the muscle and heart, suggesting increased lipid utilization. Thus, extrahepatic PPARA activity reduces systemic lipid load when hepatic lipid metabolism is impaired by elevating FAO and lipase activity in other tissues and, as a result, protects against fasting-induced hepatosteatosis. This has important clinical implications in disease states with impaired hepatic PPARA function, such as nonalcoholic steatohepatitis and nonalcoholic fatty liver disease.
Anaerobic digestion (AD) with hydrothermal (HT) pretreatment is an emerging technology for enhanced resource recovery from sewage sludge. This study investigates the speciation of Fe, P, and S during sequential HT–AD treatment of sewage sludge using sequential chemical extraction, X-ray diffraction, and X-ray absorption spectroscopy. Results suggest strong correlations between Fe and P species as well as Fe and S species, affecting the solubility and bioavailability of each other. For instance, much vivianite formed in the hydrochars after HT treatment at low temperature, while more strengite precipitated at higher HT temperature. During the subsequent AD process, microbial reduction of strengite and other Fe(III) species led to the formation of more vivianite, with concurrent P release into the solution and adsorption onto other minerals. HT pretreatment of sewage sludge had a weak effect on the sulfidation of Fe during the AD process. This work has important implications for understanding the nutrient speciation and availability in sludge-derived hydrochars and AD solids. It also provides fundamental knowledge for the selection and optimization of HT pretreatment conditions for enhanced resource recovery through sequential HT–AD process.
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