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Cell Oct 2021Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic...
Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.
Topics: Adult; Aged; Aged, 80 and over; Animals; Carcinogenesis; Cell Line; Disease Models, Animal; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Glucose-6-Phosphatase; Glycogen; Glycogen Phosphorylase; Hepatocyte Growth Factor; Hippo Signaling Pathway; Humans; Liver; Liver Neoplasms; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Neoplasm Staging; Phase Transition; Precancerous Conditions; Protein Tyrosine Phosphatases, Non-Receptor; Proto-Oncogene Proteins; Serine-Threonine Kinase 3; YAP-Signaling Proteins; Mice
PubMed: 34678143
DOI: 10.1016/j.cell.2021.10.001 -
American Journal of Nephrology 2021The remarkable ability of the body to adapt to long-term starvation has been critical for survival of primitive man. An appreciation of these processes can provide the... (Review)
Review
BACKGROUND
The remarkable ability of the body to adapt to long-term starvation has been critical for survival of primitive man. An appreciation of these processes can provide the clinician better insight into many clinical conditions characterized by ketoacidosis.
SUMMARY
The body adapts to long-term fasting by conserving nitrogen, as the brain increasingly utilizes keto acids, sparing the need for glucose. This shift in fuel utilization decreases the need for mobilization of amino acids from the muscle for purposes of gluconeogenesis. Loss of urinary nitrogen is initially in the form of urea when hepatic gluconeogenesis is dominant and later as ammonia reflecting increased glutamine uptake by the kidney. The carbon skeleton of glutamine is utilized for glucose production and regeneration of consumed HCO3-. The replacement of urea with NH4+ provides the osmoles needed for urine flow and waste product excretion. Over time, the urinary loss of nitrogen is minimized as kidney uptake of filtered ketone bodies becomes more complete. Adjustments in urine Na+ serve to minimize kidney K+ wasting and, along with changes in urine pH, minimize the likelihood of uric acid precipitation. There is a sexual dimorphism in response to starvation. Key Message: Ketoacidosis is a major feature of common clinical conditions to include diabetic ketoacidosis, alcoholic ketoacidosis, salicylate intoxication, SGLT2 inhibitor therapy, and calorie sufficient but carbohydrate-restricted diets. Familiarity with the pathophysiology and metabolic consequences of ketogenesis is critical, given the potential for the clinician to encounter one of these conditions.
Topics: Adaptation, Physiological; Gluconeogenesis; Glucose; Glycogenolysis; Homeostasis; Humans; Ketone Bodies; Ketosis; Kidney; Natriuresis; Potassium; Proteins; Sex Factors; Starvation; Uric Acid
PubMed: 34350876
DOI: 10.1159/000517305 -
The Journal of Physiology Mar 2022After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary...
After a century, it's time to turn the page on understanding of lactate metabolism and appreciate that lactate shuttling is an important component of intermediary metabolism in vivo. Cell-cell and intracellular lactate shuttles fulfil purposes of energy substrate production and distribution, as well as cell signalling under fully aerobic conditions. Recognition of lactate shuttling came first in studies of physical exercise where the roles of driver (producer) and recipient (consumer) cells and tissues were obvious. Moreover, the presence of lactate shuttling as part of postprandial glucose disposal and satiety signalling has been recognized. Mitochondrial respiration creates the physiological sink for lactate disposal in vivo. Repeated lactate exposure from regular exercise results in adaptive processes such as mitochondrial biogenesis and other healthful circulatory and neurological characteristics such as improved physical work capacity, metabolic flexibility, learning, and memory. The importance of lactate and lactate shuttling in healthful living is further emphasized when lactate signalling and shuttling are dysregulated as occurs in particular illnesses and injuries. Like a phoenix, lactate has risen to major importance in 21st century biology.
Topics: Biology; Exercise; Glycolysis; Lactic Acid; Mitochondria
PubMed: 33566386
DOI: 10.1113/JP280955 -
Cell Metabolism Feb 2021Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing...
Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.
Topics: Adult; Aged; Animals; Cells, Cultured; Female; Gluconeogenesis; Glucose; Humans; Male; Mice; Mice, Knockout; Middle Aged; Neutrophils; Young Adult
PubMed: 33306983
DOI: 10.1016/j.cmet.2020.11.016 -
Tidsskrift For Den Norske Laegeforening... Dec 2023This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common...
This clinical review will give doctors who work with children and neonates an introduction to the diagnosis and treatment of congenital hyperinsulinism, the most common cause of persistent neonatal hypoglycaemia. The condition is a rare monogenic disorder characterised by elevated insulin secretion and is a result of mutations in genes that regulate insulin secretion from pancreatic beta cells. The anabolic effect of insulin induces systemic glucose uptake and inhibits gluconeogenesis, glycogenolysis, ketogenesis and lipolysis. Low levels of glucose and ketone bodies in the blood are harmful to the central nervous system and can lead to brain damage or death. Early diagnosis and treatment of congenital hyperinsulinism are therefore crucial for a good prognosis.
Topics: Child; Infant, Newborn; Humans; Congenital Hyperinsulinism; Ketone Bodies; Insulin
PubMed: 38088279
DOI: 10.4045/tidsskr.23.0425