Publications by authors named "Sheng-Cai Lin"

Lithocholic acid (LCA) is accumulated in mammals during calorie restriction and it can activate AMP-activated protein kinase (AMPK) to slow down ageing. However, the molecular details of how LCA activates AMPK and induces these biological effects are unclear. Here we show that LCA enhances the activity of sirtuins to deacetylate and subsequently inhibit vacuolar H-ATPase (v-ATPase), which leads to AMPK activation through the lysosomal glucose-sensing pathway.

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Calorie restriction (CR) is a dietary intervention used to promote health and longevity. CR causes various metabolic changes in both the production and the circulation of metabolites; however, it remains unclear which altered metabolites account for the physiological benefits of CR. Here we use metabolomics to analyse metabolites that exhibit changes in abundance during CR and perform subsequent functional validation.

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Article Synopsis
  • Co-occurring mutations in KEAP1 and STK11 in lung cancer activate the NFE2L2/NRF2 pathway, compensating for diminished STK11-AMPK activity and aiding in metabolic adaptation.
  • Metabolic stress leads to increased levels and activation of SQSTM1/p62, crucial for the activation of both AMPK and NFE2L2, promoting tumor growth and antioxidant defenses.
  • A feedback loop exists between AMPK and SQSTM1, with SQSTM1's expression regulated by complex mechanisms involving lysosomal function and phosphorylation, which helps to explain the occurrence of co-mutated genes and indicates potential therapeutic approaches.
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The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood.

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Article Synopsis
  • - Glycolytic metabolites, like 3-phosphoglycerate (3-PGA), are not just for energy but can regulate cell fate by influencing p53 activity related to apoptosis.
  • - Low 3-PGA levels shift phosphoglycerate dehydrogenase (PHGDH) function from serine synthesis to activating p53, promoting apoptosis through interactions with proteins like AXIN and HIPK2.
  • - PHGDH mutations can either hinder or enhance p53 activation and apoptosis in liver cancer cells, with caloric restriction providing a potential method to control cancer growth by lowering glucose levels and affecting PHGDH activity.
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Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation.

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Article Synopsis
  • The study reveals that low glucose levels activate a specific version of AMPK, a protein that helps regulate energy metabolism, through the enzyme aldolase, which isn't bound to fructose-1,6-bisphosphate (FBP).
  • Researchers identified a small molecule called aldometanib that blocks FBP from binding to aldolase, leading to the activation of lysosomal AMPK and inducing beneficial metabolic effects in rodents.
  • Aldometanib demonstrated the ability to lower glucose levels without causing hypoglycemia, improve conditions like fatty liver disease, and even extend lifespan and healthspan in laboratory models, suggesting its potential as a treatment for metabolic disorders in humans.
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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by a strong production of inflammatory cytokines such as TNF and IL-6, which underlie the severity of the disease. However, the molecular mechanisms responsible for such a strong immune response remains unclear. Here, utilizing targeted tandem mass spectrometry to analyze serum metabolome and lipidome in COVID-19 patients at different temporal stages, we identified that 611 metabolites (of 1,039) were significantly altered in COVID-19 patients.

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Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex.

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Article Synopsis
  • Metformin, widely used for diabetes treatment, also shows potential benefits in anti-aging and cancer prevention, primarily activating AMPK through an unknown mechanism.
  • Recent research identifies that metformin inhibits the v-ATPase lysosomal proton pump, which is crucial for AMPK activation, by binding to a protein called PEN2.
  • Knockout experiments demonstrate that PEN2 is essential for metformin's effects on reducing liver fat and lowering blood glucose, and it also plays a role in extending lifespan in the model organism Caenorhabditis elegans.
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The AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis. Although much has been learned on how low energy status and glucose starvation activate AMPK, how AMPK activity is properly controlled in vivo is still poorly understood. Here we report that UHRF1, an epigenetic regulator highly expressed in proliferating and cancer cells, interacts with AMPK and serves to suppress AMPK activity under both basal and stressed conditions.

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The sympathetic nervous system-catecholamine-uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA).

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Remodeling of lipid metabolism has been implicated in cancers; however, it remains obscure how the lipid metabolic pathways are altered by oncogenic signaling to affect tumor development. We have recently shown that proto-oncogene tyrosine-protein kinase Src interacts with and phosphorylates the lipogenesis enzyme phosphatidate phosphatase LPIN1 to promote breast cancer development.

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Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues.

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Multidrug resistance (MDR) in cancer remains a major challenge for the success of chemotherapy. Natural products have been a rich source for the discovery of drugs against MDR cancers. Here, we applied high-throughput cytotoxicity screening of an in-house natural product library against MDR SGC7901/VCR cells and identified that the cyclodepsipeptide verucopeptin demonstrated notable antitumor potency.

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The AMPK (AMP-activated protein kinase) and TOR (target-of-rapamycin) pathways are interlinked, opposing signaling pathways involved in sensing availability of nutrients and energy and regulation of cell growth. AMPK (Yin, or the "dark side") is switched on by lack of energy or nutrients and inhibits cell growth, while TOR (Yang, or the "bright side") is switched on by nutrient availability and promotes cell growth. Genes encoding the AMPK and TOR complexes are found in almost all eukaryotes, suggesting that these pathways arose very early during eukaryotic evolution.

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Deficiency of glucose, even under sufficient amino acid supply, turns off translation and promotes catabolic processes to aid cell survival. A recent report by Yoon et al. (2020) shows that glucose is required for the full activity of the leucyl-tRNA synthetase LARS1 and maintains mTORC1 function via LARS1 to enhance translation.

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Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose.

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AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets.

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Dietary carbohydrates have been demonized for presumed negative effects on health. However, Liu et al. (2018) identify new pathways for conversion of glucose into acetate that consume reactive oxygen species.

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Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues. However, how signaling networks sense fatty acids and connect to the stimulation of lipid synthesis remains elusive. Here, we show that homozygous knock-in mice carrying a point mutation at the Ser phosphorylation site of acetyltransferase Tip60 (Tip60 ) display remarkably reduced body fat mass, and Tip60 females fail to nurture pups to adulthood due to severely reduced milk TAGs.

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