IL-6 is able to suppress insulin signaling by stimulating expression of SOCS3 in the liver (221). Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, Shioda T, Hansen M, Yang F, Niebergall LJ, Vance DE, Tzoneva M, Hart AC, Naar AM. Both malonyl-CoA and NADPH are used as precursors to synthesize palmitic acid (a 16-carbon fatty acid) by fatty acid synthase (FAS). Alternatively, pyruvate is used to synthesize fatty acids through lipogenesis (Fig. Insulin binds to the insulin receptor to activate the PI 3 K/AKT/PKB pathway, which stimulates glycogen . Expression of hepatic PPAR is repressed by the hairy enhancer of split 1 (HES-1) in the liver (74). Surprisingly, genetic deletion of LXRb has been reported to impair the ability of GR to stimulate the expression of gluconeogenic genes and HGP (197). Sloop KW, Cao JX, Siesky AM, Zhang HY, Bodenmiller DM, Cox AL, Jacobs SJ, Moyers JS, Owens RA, Showalter AD, Brenner MB, Raap A, Gromada J, Berridge BR, Monteith DK, Porksen N, McKay RA, Monia BP, Bhanot S, Watts LM, Michael MD. Kupffer cells are a major source of cytokines, and depletion of Kupffer cells improves NAFLD and insulin resistance in the liver (81). Insulin and glucagon (video) Fructose-2,6-bisphosphate (F-2,6-P2), which is derived from G6P (Fig. Vega RB, Huss JM, Kelly DP. Glucose produced from the liver contributes significantly to hyperglycemia in humans with type 2 diabetes (41, 153, 164). UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. CGI-58, an endogenous activator of ATGL, binds to perilipins under basal conditions; catecholamine hormones stimulate phosphorylation of perilipins which releases CGI-58, allowing it to activate ATGL and stimulate lipolysis (63, 122). Sakiyama H, Wynn RM, Lee WR, Fukasawa M, Mizuguchi H, Gardner KH, Repa JJ, Uyeda K. Regulation of nuclear import/export of carbohydrate response element-binding protein (ChREBP): interaction of an alpha-helix of ChREBP with the 14-3-3 proteins and regulation by phosphorylation. Xu E, Charbonneau A, Rolland Y, Bellmann K, Pao L, Siminovitch KA, Neel BG, Beauchemin N, Marette A. Hepatocyte-specific Ptpn6 deletion protects from obesity-linked hepatic insulin resistance. Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Insulin and Glucagon - csudh.edu Systemic insulin resistance is a causal factor for the development of NAFLD, and lipid accumulation in the liver further promotes hepatic insulin resistance, thus forming a vicious cycle. CREBH is an ER-membrane protein, and its levels are higher in the fasted state (128). Glucose Metabolism and Regulation: Beyond Insulin and Glucagon Both SREBP-1c and SREBP-2 are abundantly expressed in the liver (78). G6P, a glycolytic intermediate, binds to and activates ChREBP in hepatocytes (47). AMPK phosphorylates CRTC2 and blocks nuclear translocation of CRTC2, thus inhibiting the ability of CRTC2 to promote hepatic gluconeogenesis (115). Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Additionally, F-2,6-P2, a G6P-drived product, also stimulates nuclear translocation of ChREBP (7). SIRT5 deacetylates and activates CPS-1 (179). The LKB1/AMP pathway suppresses hepatic glucose production. The Farnesoid X Receptor Inhibits the Transcriptional Activity of the Carbohydrate Response Element Binding Protein in Human Hepatocytes -- R2. PKA also phosphorylates and activates inositol-1,4,5-triphosphate receptors (IP3Rs), thus increasing the release of Ca2+ from the ER into the cytoplasm (Fig. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Liver-produced glucose and ketone bodies are delivered to muscle and other extrahepatic tissues and are used as metabolic fuels during fasting and exercise; in return, skeletal muscle provides the liver with lactate and amino acids which serve as gluconeogenic substrates for hepatocytes to synthesize glucose. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. PPAR also stimulates the expression of Cidec, a lipid droplet protein (160). Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Liver-specific deletion of G results in glucagon resistance, hypoglycemia, and reduced expression of gluconeogenic genes (34). Sumara G, Sumara O, Kim JK, Karsenty G. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. SREBP-1b promotes both fatty acid and cholesterol synthesis (78). In the fed state, or postprandial, elevated glucose levels trigger the release of insulin from the pancreas. FATP2 also has very long-chain acyl-CoA synthetase activity (56, 245). Hypothalamic neurons are also able to directly sense glucose, amino acids, and lipids, and they suppress HGP by increasing vagal nervous outflow to the liver (119, 120, 186). Glucagon stimulates dephosphorylation and nuclear translocation of HDAC4/5/7 which interact with both HDAC3 and FOXO1 at the promoters of FOXO1 target genes (Fig. 2A) (46). IRS proteins and the common path to diabetes. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. This hyperglucagonemia leads to hyperglycemia through the activation of hepatic glycogenolysis and gluconeogenesis . Tobin KA, Ulven SM, Schuster GU, Steineger HH, Andresen SM, Gustafsson JA, Nebb HI. Hesse (Hessen) | German states - IamExpat in Germany The gut is anatomically connected to the liver by the portal vein circulation. GH and glucocorticoids are important counterregulatory hormones. Hepatic lipogenesis is low in the fasted state and high in the fed state. In fact, exogenous glucagon given under fed conditions did robustly stimulate insulin secretion and lower glycemia. Inhibition of phosphatidylcholine biosynthesis reduces phosphatidylcholine pools in hepatocytes, which promotes SREBP-1 cleavage and activation (258). Jelen S, Gena P, Lebeck J, Rojek A, Praetorius J, Frokiaer J, Fenton RA, Nielsen S, Calamita G, Rutzler M. Aquaporin-9 and urea transporter-A gene deletions affect urea transmembrane passage in murine hepatocytes. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Liver-specific loss of long chain acyl-CoA synthetase-1 decreases triacylglycerol synthesis and beta-oxidation and alters phospholipid fatty acid composition. Glucose is a potent activator of ChREBP. Hepatocyte-specific deletion of FOXO1 decreases both glycogenolysis and gluconeogenesis in fasted mice, leading to hypoglycemia (158). Cheung GW, Kokorovic A, Lam CK, Chari M, Lam TK. Fatty acids are also incorporated into phospholipids, which are an essential component of cell membranes, and the surface layer of lipid droplets, VLDL, and bile particles. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Fatty Acid Metabolism - an overview | ScienceDirect Topics The increase in insulin/glucagon ratio switches off the stimulatory effects of glucagon on glucose production by the liver, thus facilitating the suppressive effects of insulin. Proinflammatory cytokines activate the IKK and the JNK pathways which inhibit insulin signaling (22, 79). LXRbeta is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. This can happen in two ways: either converting glucose--> pyruvate (glycolysis) or by converting glucose-->glycogen (glucogenesis). Intestinal cholecystokinin controls glucose production through a neuronal network. Takeaway. Orphan nuclear receptor small heterodimer partner negatively regulates growth hormone-mediated induction of hepatic gluconeogenesis through inhibition of signal transducer and activator of transcription 5 (STAT5) transactivation. Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Molusky MM, Li S, Ma D, Yu L, Lin JD. We recently reported that inflammatory pathways enhance the ability of glucagon to stimulate gluconeogenesis, contributing to hyperglycemia and glucose intolerance in mice with obesity (36, 234). PPAR is a nuclear receptor family member activated by a subtype of LCFAs and phosphatidylcholines (30). Glucose stimulates acetylation of PEPCK-C by p300, which promotes PEPCK-C ubiquitination and degradation (97). FXR is acetylated by p300 and deacetylated by SIRT1, and SIRT1-mediated deacetylation increases FXR activity (103). Both SIRT3 and SIRT5 are located in mitochondria, and their activity is higher in the fasted state (69, 179). Fed-state metabolism under the influence of insulin promotes glucose metabolism by cells Stimuli for Insulin Secretion - Increased glucose concentrations - Increased amino acids concentrations - Feedforward effects of GI hormones --Parasympathetic activity --Sympathetic activity Multiple Stimuli for Insulin Release Wang Y, Inoue H, Ravnskjaer K, Viste K, Miller N, Liu Y, Hedrick S, Vera L, Montminy M. Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Activation of glucose sensing pathways in the brain also suppresses SCD1 expression, lipogenesis, and VLDL secretion in the liver (118). Ubiquitin-specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11beta-hydroxysteroid dehydrogenase 1. Insulin stimulates acetylation of glycogen phosphorylase, which promotes dephosphorylation and inhibition of glycogen phosphorylase by protein phosphatase 1, thus suppressing glycogenolysis (288). Caron S, Samanez CH, Dehondt H, Ploton M, Briand O, Lien F, Dorchies E, Dumont J, Postic C, Cariou B, Lefebvre P, Staels B. Obesity and NAFLD are associated with ER stress, which promotes insulin resistance, in the liver (193). Deletion of USF-1 or USF-2 markedly suppresses carbohydrate-stimulated expression of FAS in the liver during a fasting/feeding transition (28). FXR knockout mice have higher levels of TAG in both the circulation and the liver (237). In contrast, XBP1 is able to bind to FOXO1 and target FoxO1 for degradation, thus inhibiting the hepatic gluconeogenesis (296). If you get a 3-month supply of insulin, your costs can't be more than $35 for each month's supply of each covered insulin. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. These immune cells as well as hepatocytes secrete numerous cytokines which regulate hepatocyte metabolism in an autocrine/paracrine fashion. 3). After digestion of a meal, in the fed state, glucose levels are sensed by pancreatic cells that secrete insulin while secretion of glucagon from pancreatic cells is suppressed. Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA. In the cytoplasm, acetyl-CoA is carboxylated by acetyl-CoA carboxylase (ACC) to form malonyl-CoA (Fig. Jeong JY, Jeoung NH, Park KG, Lee IK. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Restoration of LepRb specifically in POMC neurons, an important subpopulation of hypothalamic neurons, markedly decreases hyperglucagonemia, leading to reduction in HGP and blood glucose levels (15). 1). Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. These counterregulatory hormones bind to their cognate G protein-coupled receptors and activate protein kinase A (PKA) by increasing intracellular cAMP levels. Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, Cho YR, Kim JK, Kahn BB, Neel BG, Bence KK. Knockdown of SIRT1 in the liver decreases hepatic gluconeogenesis in mice with obesity (53, 217). Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase. HDAC6 dephosphorylates HSP90 and promotes GR-HSP90 complex assembly, and deletion of HDAC60 blocks ligand-induced nuclear translocation of GR and GR-stimulated expression of gluconeogenic genes PEPCK-C, G6Pase, FBPase, and pyruvate carboxylase in the liver (273). Hepatocytes also obtain fatty acids from the bloodstream, which are released from adipose tissue or absorbed from food digestion in the GI. Systemic deletion of ACC1 causes embryonic death (3). Hepatic energy metabolism is largely controlled at the genomic levels by numerous transcription factors and coregulators. CPT-1 activity is inhibited by malonyl-CoA. 3). Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Decreased liver fatty acid binding capacity and altered liver lipid distribution in mice lacking the liver fatty acid-binding protein gene. Regulation of glycolysis and gluconeogenesis Sos BC, Harris C, Nordstrom SM, Tran JL, Balazs M, Caplazi P, Febbraio M, Applegate MA, Wagner KU, Weiss EJ. An FGF21-Adiponectin-Ceramide Axis Controls Energy Expenditure and Insulin Action in Mice. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierkes disease. These results indicate that insulin may be an important promoter of chick embryonic growth by the anabolic drive to promote protein deposition. HSL is also able to hydrolyze retinyl esters and cholesterol esters (285). Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. In the fasted state, fatty acids are oxidized mainly in the mitochondria to generate energy supply as well as ketone bodies. Metabolic Map. Role of insulin and glucagon in maintaining blood glucose homeostasis. SHP in turn inhibits the ability of STAT5 to bind to PEPCK-C and PDK4 promoters (109, 110), thus inhibiting hepatic gluconeogenesis. ChREBP levels are elevated in obese mice, and genetic deletion of ChREBP, or liver-specific inhibition of ChREBP, decreases hepatic lipogenesis and steatosis in ob/ob mice (45, 83). +, stimulated by glucagon; -, inhibited by glucagon. PKA phosphorylates and activates glycogen phosphorylase directly or indirectly by phosphorylating and activating phosphorylase kinases. Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. . Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Multiple nutrient, hormonal, and neuronal signals have been identified to regulate glucose, lipid, and amino acid metabolism in the liver. Disruption of glutamatergic transmission in the ventromedial hypothalamus by deleting VGLUT2 in SF1-expressing neurons decreases secretion of glucagon from pancreatic cells in the fasted state, resulting in a decrease in hepatic gluconeogenesis and blood glucose levels (251). In the fasted state, G6P is transported into the endoplasmic reticulum (ER) and dephosphorylated by glucose-6-phosphatase (G6Pase) to release glucose. Acetylation states of these enzymes are regulated by nutrient availability (292). Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. A role of DNA-PK for the metabolic gene regulation in response to insulin. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, Ronan J, Liu F, Roy RS, Zhu L, Charron MJ, Zhang BB. Circadian clock genes have been reported to regulate hepatic gluconeogenesis. Knockdown of CREB in the liver reduces HGP in rodents with type 2 diabetes (52). Mitochondrial SIRT3, which is upregulated in the fasted state, deacetylates and activates LCAD in the liver, thus promoting fatty acid oxidation (76). SREBP activation is also subjected to posttranslational modifications. Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM. One year later, in 1923, a hyperglycemic factor Moreover, glucagon and catecholamines (e.g. Insulin receptors bind to IRS1 and IRS2 and phosphorylate them on tyrosine residues (223, 272). Effects of insulin and glucagon throughout the body. Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, Gutierrez-Juarez R, Ang M, Schwartz GJ, Lam TK. 2B) (146). Glucose is hydrolyzed into pyruvate through glycolysis. It stimulates the expression of SHP, a transcription repressor which inhibits the expression of Cyp7a (23, 237). Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferre P, Foufelle F. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. Hepatocyte growth factor receptor Met is able to form a hybrid complex with insulin receptors in the liver to promote insulin signaling (55). We hypothesized that the elevated glycemia seen in the fed state would allow glucagon to stimulate insulin secretion and reduce blood glucose. Rodents treated with GC have unaltered insulin/glucagon ratio from the fasted state to the fed state. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Inhibition of liver CREB, by liver-specific transgenic overexpression of a dominant negative form of CREB, decreases the expression of PEPCK-C, G6Pase, and PGC-1, leading to reduced hepatic glucose production (HGP) and hypoglycemia (75). The plasma insulin to glucagon molar ratio of incubation from 14E to 17E ranged from 2 to 4, and was significantly higher than at any other time during incubation. Genomic recruitment of HDAC3 displays a circadian rhythm and is controlled by circadian clocks, and the rhythmic recruitment of HDAC3 regulates circadian rhythm of hepatic lipogenesis (59). Role for PPARgamma in obesity-induced hepatic steatosis as determined by hepatocyteand macrophage-specific conditional knockouts. Professor Herrmann makes an important point. FABP4 (also called aP2) is secreted by white adipose tissue, and secretion is higher in the fasted state (25). Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. Yamashita H, Takenoshita M, Sakurai M, Bruick RK, Henzel WJ, Shillinglaw W, Arnot D, Uyeda K. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Solved Insulin and glucagon oppositely control glucose National Library of Medicine Puri V, Ranjit S, Konda S, Nicoloro SM, Straubhaar J, Chawla A, Chouinard M, Lin C, Burkart A, Corvera S, Perugini RA, Czech MP. Hepatic CREBH stimulates the expressing of LPL coactivators (e.g Apoa4, Apoa5, and Apoc2) and suppresses the expression of LPL inhibitor Apoc3, thus promoting plasma TAG clearance from the circulation (125). The null mice have a compensatory increase in the expression of sterol carrier protein-2 (SCP-2) which also binds LCFAs (156). ChREBP binds to Max-like protein X (Mlx), and the heterodimer acts as a functional transcription factor (244). Fan Y, Menon RK, Cohen P, Hwang D, Clemens T, DiGirolamo DJ, Kopchick JJ, Le Roith D, Trucco M, Sperling MA. Glucagon also stimulates phosphorylation of IRE1 by PKA, and silencing of hepatic IRE1 impairs HGP (155). LXR activation also suppresses GR expression in hepatocytes (147). It is also metabolized to generate pyruvate through glycolysis. ChREBP is phosphorylated and inhibited by PKA, and dephosphoralated and activated by PP2A (102). The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. SHP, the main transcriptional target of FXR, suppresses the ability of LXR to stimulate the expression of lipogenic SREBP-1 (269). Ren D, Li M, Duan C, Rui L. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Ozcan L, Wong CC, Li G, Xu T, Pajvani U, Park SK, Wronska A, Chen BX, Marks AR, Fukamizu A, Backs J, Singer HA, Yates JR, 3rd, Accili D, Tabas I. Calcium Signaling through CaMKII Regulates Hepatic Glucose Production in Fasting and Obesity. acids and glycerol from adipose tissue and amino acids from muscle. FGF15/19 stimulates the ERK/RSK pathway by activating its receptors FGFR4 and -klotho, and activated RSK phosphorylates and inactivates GSK-3, a negative regulator of glycogen synthase (112). Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. Morris DL, Cho KW, Zhou Y, Rui L. SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. 8600 Rockville Pike 2A) (136). Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Young SG, Zechner R. Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. However, hepatocyte-specific deletion of C/EBP does not affect the expression of PEPCK-C and G6Pase, and the mutant mice have normal blood glucose levels (89). PGC-1 is a well-characterized PPAR coactivator which promotes oxidation (256). Rajala MW, Scherer PE. NADPH is required for lipogenesis and biosynthesis of other bioactive molecules. Insulin and Glucagon: How They Impact Blood Sugar C-reactive protein (CRP), an acute phase protein secreted by the liver, inhibits insulin signaling through the ERK pathway in primary hepatocytes and inhibits the ability of insulin to suppress HGP in rats (277). Systemic deletion of CRTC2 impairs both the expression of liver gluconeogenic genes and the ability of glucagon to stimulate glucose production in hepatocytes (123, 264). Of the amino acids transported to liver from muscle during exercise and starvation, Ala predominates. Mice with hepatocyte-specific deletion of PEPCK-C are viable but are unable to produce glucose from lactate and amino acids via gluconeogenesis, leading to accumulation of TCA cycle intermediates in hepatocytes and hepatic steatosis in the fasted state (21). Deletion of SH2B1 results in leptin resistance, insulin resistance, obesity, NAFLD, and type 2 diabetes (171, 212, 213). Long-chain acyl-CoA dehydrogenase (LCAD) activity is also regulated through posttranslational modifications. Deletion of Elovl6 protects against hepatic steatosis and liver inflammation in mice fed an atherogenic high fat diet (AHF); conversely, liver-specific overexpression of Elovl6 increases AHF-induced fatty liver and liver fibrosis (161). Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. In this postprandial or "fed" state, the liver takes in more glucose from the blood than it releases. Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Insulin signaling is negatively regulated by protein phosphatases, including PTP1B and Shp-1. Hepatic gluconeogenesis is lower in CaMKII null mice, and liver-specific overexpression of CaMKII increases gluconeogenesis (192). Pathways of hepatic glycogen formation in humans following ingestion of a glucose load in the fed state. FATP2 also mediates liver fatty acid uptake, and knockdown of FATP2 in the liver decreases NEFA uptake and reduces high fat diet (HFD)-induced hepatic steatosis (56). Hepatocyte-specific deletion of JNK1 results in liver inflammation and steatosis in mice fed a normal chow diet (220). pyruvate, oxaloacetate, fumarate, succinyl-CoA, or -ketoglutarate) which serve as precursors for gluconeogenesis. CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required for the maintenance of glucose homeostasis. Falcon A, Doege H, Fluitt A, Tsang B, Watson N, Kay MA, Stahl A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. PPAR agonist treatments correct hepatic steatosis and hypoglycemia in mice with liver-specific deletion of FAS that are fed a zero-fat, high carbohydrate diet (31). Deletion of FGF19 or its receptor FGFR4 increases gluconeogenesis and blood glucose levels (202). Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino-Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ. The fasted/starved state; glucagon predominates: Major sites of glucagon action on fuel metabolism. CREBH binds to CRTC2 and promotes the expression of gluconeogenic genes, including PEPCK-C and G6Pase (128). Systemic deletion of glucagon receptors decreases blood glucose levels and improves glucose tolerance (62, 196). The NTS in turn suppresses HGP via the hepatic branch of vagus nerve fibers (262). Lustig Y, Ruas JL, Estall JL, Lo JC, Devarakonda S, Laznik D, Choi JH, Ono H, Olsen JV, Spiegelman BM. Gluconeogenic enzymes are regulated by posttranslational modifications and/or allosteric regulation. Chen W, Chen G, Head DL, Mangelsdorf DJ, Russell DW. Liver-specific deletion of JAK2 or STAT5 also causes GH resistance in the liver and increases compensatory GH secretion, thus increasing adipocyte lipolysis and hepatic steatosis (42, 240). FATP2 and FATP4 reside mainly in peroxisomes and mediate transport of long-chain fatty acids (LCFAs) into peroxisomes (56, 245). Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, Nicol CJ, Vinson C, Gonzalez FJ, Reitman ML. FGF21 stimulates both lipolysis and the expression and secretion of adiponectin by adipose tissue (6, 66, 77, 142). A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. FAS products are believed to serve as endogenous ligands for PPAR and stimulate fatty acid oxidation in the liver (30, 31). In the fed state, G6P acts as a precursor for glycogen synthesis (Fig. Nader N, Ng SS, Wang Y, Abel BS, Chrousos GP, Kino T. Liver x receptors regulate the transcriptional activity of the glucocorticoid receptor: implications for the carbohydrate metabolism. Wang Y, Vera L, Fischer WH, Montminy M. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Circulating FGF15/19 levels increase after food ingestion (202). FOXO1 interacts with C/EBP, and these two proteins act cooperatively to promote gluconeogenesis (229). 3.1: Fed and fasted states - Medicine LibreTexts Insulin stimulates phosphorylation of upstream stimulatory factor-1 (USF-1) through DNA-PK (274). PGC-1 is acetylated by GCN5, and acetylation decreases the ability of PGC-1 to activate gluconenogenic genes (133).
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