Altered lipid and bile acid metabolism in Glycogen Storage Disease type 1a:
pathophysiological mechanisms and therapeutic opportunities
Hoogerland, Joanne
DOI:
10.33612/diss.131695607
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Publication date: 2020
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Hoogerland, J. (2020). Altered lipid and bile acid metabolism in Glycogen Storage Disease type 1a: pathophysiological mechanisms and therapeutic opportunities. University of Groningen.
https://doi.org/10.33612/diss.131695607
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CHAPTER
General Introduction
Major chronic diseases, such as obesity and type 2 diabetes, are increasingly common in societies around the world. Obesogenic environments, with excess availability of high-caloric foods combined with a sedentary lifestyle, facilitate the development of a disturbed energy metabolism that underlies the etiologies of these diseases. Yet, it should be realized that the different components of habitual diets can not be considered as interchangeable currencies, i.e., as calories. A ‘regular’ meal, consisting of proteins, fats, and carbohydrates, is broken down in the alimentary tract into amino acids, fatty acids and simple sugars, such as glucose. These metabolites are absorbed into the circulation and can be used by the various cell types in the body as energy sources or building blocks but, to a variable degree, can also act as signaling molecules that modulate cellular metabolism. Unbalanced consumption of foods containing high sugar and/or fat definitively contributes to obesity and type 2 diabetes. Yet, there are also diseases that are caused by an inherited inability of the body to appropriately regulate amino acid, fatty acid or glucose metabolism, commonly referred to as Inborn Errors of Metabolism. Glycogen Storage Disease type Ia (GSD Ia) is an inherited disorder of glucose metabolism. This thesis addresses the (patho)physiological consequences of disturbed glucose metabolism in GSD Ia, which can provide new insights in the pathophysiology of other metabolic diseases, such as type 2 diabetes.
Glucose is, in addition to fatty acids and amino acids, a major energy source and metabolic fuel for complex organisms. After intake of food and its digestion, glucose molecules are taken up by enterocytes and transported into the blood stream. Rising blood glucose levels after a meal result in insulin production and -release by the pancreas, which stimulates tissue glucose uptake while suppressing glucose production by the body, referred to as endogenous glucose production. Blood glucose levels are tightly regulated, as both low and high plasma glucose levels are detrimental (1). During the fasting state, when blood glucose levels are low, most cells switch from glucose to fatty acids and amino acids as alternate energy sources. Neurons and erythrocytes, however, fully rely on glucose and acute or permanently low blood glucose levels (hypoglycemia) may damage the nervous system, leading to cognitive impairment. On the other hand, high glucose levels (hyperglycemia) as occur in uncontrolled diabetes, result in complications such as retinopathy and nephropathy (2). Therefore, to ensure optimal functioning, blood glucose concentrations should be maintained between 4-8 mM during the consecutive feeding and fasting cycles. To achieve this goal, the body possesses glucose sensing systems that control the activity of biochemical pathways for glucose utilization and –production. Besides tuning its own metabolism, changes in glucose availability also attenuate other metabolic pathways, such as fatty acid- and cholesterol synthesis, both via substrate supply and intracellular signaling. Studies described in this thesis primarily focus on the liver, that represents a central organ in glucose homeostasis, as it converges glucose
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consumption, storage, and production. These functions are executed by hepatocytes, which account for about 70% of the total liver cell content (3). Figure 1 provides a schematic overview of hepatic glucose metabolism.
Hepatic glucose metabolism
Hepatic glucose uptake during postprandial (fed) conditions is mainly facilitated by the high-capacity transporter glucose transporter 2 (GLUT2; SLC2A9) in hepatocytes (4). As GLUT2 only saturates at glucose concentrations above 30 mM, the concentration of intrahepatic glucose rapidly equilibrates to blood glucose concentrations (5). In the cytoplasm, glucose is phosphorylated to glucose-6-phosphate (G6P) by hexokinases (HKs). HKs type 1-3 are expressed by all cell types, have a high glucose affinity and are inhibited by their product G6P (6). In contrast, HK type 4 (also known as glucokinase; GCK) is selectively expressed by hepatocytes, pancreatic β-cells and neurons (7). HK type 4 has a low affinity for glucose and is not inhibited by G6P and its activity consequently increases with rising blood glucose levels. Cells expressing HK type 4 are sensitive to changes in blood glucose levels, allowing them to respond effectively to fluctuations in glycemia (6,8,9). Thus, by expressing GLUT2 and GCK, hepatocytes are sensitive to circulating blood glucose levels, and are able to accommodate glucose consumption, storage and production to the blood glucose concentration.
Hepatocytic G6P is a precursor for different biochemical pathways (10). First, it can be immediately dephosphorylated back to glucose by the glucose-6-phosphatase (G6Pase) complex (11), referred to as ‘futile cycling’ of glucose (12). Next, in the
Acetyl-CoA Glycolysis TG Glucose GLUT2 G6Pase GCK G6P Glycogen GS GP Pyruvate ATP Amino acids Citrate NADPH, PPP substrates PPP TCA cycle Gluconeogenesis Lactate Figure 1. Schematic overview of hepatic glucose metabolism. GLUT2, glucose transporter 2; GCK, glucokinase; G6Pase, glucose-6-phosphatase; GS, glycogen synthase; GP, glycogen phosphorylase; G6P, glucose-6-phosphate; PPP, pentose phosphate pathway; TG, triglycerides
Figure 1. Schematic overview of hepatic glucose metabolism. GLUT2, glucose transporter 2; GCK,
glucokinase; G6Pase, glucose-6-phosphatase; GS, glycogen synthase; GP, glycogen phosphorylase; G6P, glucose-6-phosphate; PPP, pentose phosphate pathway; TG, triglycerides.
postprandial state, G6P is partly converted by glycogen synthase (GYS) into glycogen and stored in the liver. G6P can also be metabolized into pyruvate through glycolysis. The last step in this pathway is catalyzed by liver pyruvate kinase (PKLR). Pyruvate can subsequently be used as a substrate in the tricarboxylic acid (TCA) cycle to generate adenosine triphosphate (ATP) or it can be converted into lactate which is then released into the circulation. Lastly, G6P can be metabolized via the pentose phosphate pathway (PPP) to generate 6-phosphogluconate, ribulose 5-phosphate and NADPH. The PPP contributes to glycolysis, gluconeogenesis and DNA synthesis as ribulose 5-phosphate serves as a precursor for glyceraldehyde 3-phosphate (G3P) and nucleotide synthesis. NADPH, on the other hand, supports lipogenesis as reducing equivalent, and is protective against oxidative damage by reducing hydrogen peroxide via the glutathione system. G6P is thus an important crossroad molecule, as it is a substrate for several metabolic pathways.
To maintain blood glucose levels in the post-absorptive (fasted) state, the body switches from glucose consuming and storing pathways towards glucose producing pathways. In cases of prolonged fasting, hepatic glycogen stores are depleted to produce G6P and glucose via glycogen phosphorylase (PYGL) and glycogen debranching enzyme (AGL). In addition, glucose can be synthesized de novo from gluconeogenic precursors in liver and, to a lesser extent, in kidney and intestine. During gluconeogenesis, pyruvate is converted to oxaloacetate by pyruvate carboxylase (PC), and subsequently to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase (PEPCK). Via multiple steps phosphoenolpyruvate is converted into G3P. Aldolase B catalyzes the reaction of G3P to fructose-1,6-phosphate and the irreversible reaction of fructose-1,6-phosphate to fructose-6-phosphate (F-6-P) is catalyzed by fructose-1,6-biphosphatase (F1,6bisPase). Finally, F-6-P is isomerized to G6P. Gluconeogenesis and glycogenolysis both result in the formation of G6P, which is then hydrolyzed to glucose and phosphate by the glucose-6-phosphatase (G6Pase) complex (11). This complex, located in the endoplasmic reticulum (ER), consists of the glucose-6-phosphate transporter (SLC37A1; G6PT) and the glucose-6-phosphatase (G6PC) enzyme. G6PC1 (G6Pase-α) is exclusively expressed in the liver, kidney and intestine, and is coupled to G6PT in order to import G6P into the ER, to hydrolyze it to glucose, and to export it to the bloodstream via a membrane traffic-based pathway (13–15). Paralogs of G6PC1 are G6PC2 and G6PC3 (G6Pase-β). G6PC2 is solely expressed in pancreatic islets and has no phosphohydrolase activity. In contrast to G6PC1 and G6PC2, G6PC3 is ubiquitously expressed. Coupled to G6PT, G6PC3 acts in a similar manner as the G6PC1/G6PT complex by hydrolyzing G6P to glucose, although with an approximately 6-fold lower reaction rate (16). G6PC3 is required for adequate neutrophil function, as its deficiency leads to neutrophil dysfunction and malformations (14,17–19). G6PC3 deficiency has no impact on glucose homeostasis (19,20), thus G6PC1 is the key enzyme that catalyzes the final step in gluconeogenesis
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and glycogenolysis hence ensuring adequate glycemic control during fasting.Intrahepatic glucose-sensing systems
In order to ensure proper switching between glucose producing or –consuming pathways and maintain blood glucose within its physiological range, glycemia is monitored by extra- and intrahepatic glucose-sensing systems. Extrahepatic, hormonal regulation of glucose metabolism by insulin and glucagon shifts the balance between glycolysis and gluconeogenesis, and between glycogen production and breakdown in the liver. An overview of these extrahepatic glucose sensing systems can be found elsewhere (1,21,22). Intrahepatic glucose-sensing systems comprise allosteric regulation, transcriptional regulation, as well as post-translational modifications (10), as will be explained in detail below.
Glucose-sensitive transcription factor ChREBP
The transcription factor carbohydrate response element binding protein (ChREBP; MLXIPL) is a major glucose sensor expressed in hepatocytes (23). It is activated by intermediates of glucose metabolism and it exerts a signaling function by regulating the expression of enzymes involved in glycolysis (i.e., GLUT2, PKLR), gluconeogenesis (i.e., G6PC), de novo lipogenesis (i.e., fatty acid synthase; FASN, acetyl-CoA carboxylase; ACC1) (24–26) and very low-density lipoprotein (VLDL) assembly (i.e., microsomal triglyceride transfer protein; MTTP) (27,28). In addition, in vitro studies in human hepatoma cells showed that ChREBP controls the expression of genes involved in transport, development and cell motility, although the physiological relevance for hepatocytes in vivo remains to be established (29). ChREBP, consisting of a low glucose inhibitory domain (LID), and a glucose response conserved element (GRACE) has two isoforms; ChREBPα and ChREBPβ. ChREBPα represents the full-length protein, whereas the ChREBPβ protein is a shorter isoform, lacking the LID domain (30,31). As the LID domain is responsible for inhibiting ChREBP activity under low glucose concentrations, ChREBPβ can act independently of glucose concentrations once it is activated (30,31). ChREBP regulates its own expression through a carbohydrate response element (ChoRE) on the proximal promotor of ChREBPβ, thus generating a potent feed forward loop (31,32). Although ChREBPβ is considered to be the most transcriptionally active isoform, isoform-specific differences between ChREBPα and –β concerning activation and transcriptional targets remain as yet elusive.
ChREBP activation is complex and involves several mechanisms (33). Firstly, ChREBP is activated by posttranslational modifications, e.g., phosphorylation/ dephosphorylation, acetylation and O-linked β-N-acetylglucosaminylation (O-GlcNAcylation). According to the classical view, cytosolic ChREBPα is dephosphorylated by protein phosphorylase 2A (PP2A) upon stimulation by glucose
and is subsequently translocated to the nucleus. Here, ChREBP binds to ChoREs in the promotor regions of glucose-sensitive genes, while also promoting the transcription of ChREBPβ. Under low glucose conditions, ChREBPα translocation and activity are inhibited by phosphorylation via cAMP-dependent protein kinase (PKA) and AMP-activated protein kinase (AMPK) (34–36). Next to phosphorylation/ dephosphorylation, nuclear acetylation of ChREBP and association with histone acetyltransferase (HAT) coactivator p300 promote its recruitment and binding to the DNA (37). In addition, O-GlcNAcylation stimulates ChREBP by increasing its protein levels and transactivation (38–40). Secondly, ChREBP is activated by glycolytic and PPP intermediates. X5P, a PPP intermediate, stimulates PP2A-mediated ChREBP dephosphorylation, promoting its nuclear translocation and transcriptional activity (35). In addition, glycolytic metabolites G6P and fructose-2,6-bisphosphate (F2,6bisP) promote ChREBP transactivation (41–43). Although activation of ChREBP by G6P and F2,6bisP likely involves allosteric regulation and post-transcriptional modifications, the exact mechanisms are still unknown. Thirdly, ChREBP expression and activity are regulated by other nuclear receptors. Both liver X receptor (LXR) and thyroid hormone (TR) can bind to the ChREBP gene promotor and activate its transcription and activity (44–47). Farnesoid X receptor (FXR), on the other hand, interacts with the ChREBP protein, thereby modulating transcription of ChREBP genes involved in glycolysis and lipogenesis (48).
Hepatic GCK-ChREBP signaling
The glucose-sensitive enzyme GCK controls the flux of glucose into hepatocytes (49,50). Its activity and expression increases with rising blood glucose levels, which has been proposed to be mediated by the insulin-activated transcription factor sterol regulatory element binding protein (SREBP1c) (51,52). However, discrepancies between findings in vivo and in vitro concerning insulin-mediated GCK transcription by SREBP1c have challenged this view. Other transcription factors, i.e., PPARγ, LXR, and LRH-1 have been proposed to contribute to GCK expression and activation (52– 56). Glycolytic metabolites fructose-1-phosphate and F-6-P, respectively, inhibit and stimulate release of GCK from the nucleus to the cytosol by binding to glucokinase regulatory protein (GCKR) (8,57). As GCK-dependent synthesis of glycolytic metabolites (G6P, X5P, F2,6bisP) is crucial for ChREBP activation, the GCK-ChREBP axis is considered as the major hepatic glucose-sensing system (53,58,59).
Glucose-sensitive post-translational modifications
Post-translational modifications allow for rapid adaptive response of regulatory proteins to environmental changes. The metabolic state of the cell is reflected by intracellular intermediates, such as acetyl-CoA, which can modify metabolic enzymes (60,61). Importantly, post-transcriptional modifications of metabolic enzymes allow for feed-forward and feed-back regulation of biochemical pathways in response to
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the metabolic state (62). Modification of histone proteins alters the accessibility ofthe chromatin for transcription factors, hence altering transcriptional activity. Two glucose-sensitive post-translational modifications that likely contribute to hepatic glucose sensing are acetylation and O-GlcNAcylation (63–67). In case of protein acetylation, the acetyl group of acetyl-CoA is transferred to specific lysine residues of the protein. This process is facilitated by lysine acetyltransferases (KATs) and the reverse reaction is mediated by either histone deacetylases (HDACs) or sirtuins. Interestingly, glucose metabolism and availability is involved in histone acetylation via ATP-citrate lyase (ACLY), the enzyme that converts glucose-derived citrate into acetyl-CoA (61). Although fatty acid oxidation also results in production of acetyl-CoA, it was at first suggested that only nucleocytoplasmic, and not mitochondrial, acetyl-CoA promotes histone acetylation (61). However, this view was recently challenged as lipid-derived carbons were found to be used for histone acetylation, as shown by a stable isotope tracing technique (68). In vitro, ACLY-dependent production of acetyl-CoA determines the total amount of histone acetylation and contributes to post-translational regulation of genes involved in glucose metabolism (61,69–72). Future work will reveal how different metabolic pathways and protein acetylation interact/converge to optimize cellular responses. The substrate for O-GlcNAcylation, UDP-N-acetylglucosamine (UDP-GlcNAc), is synthesized by the hexosamine biosynthesis pathway from F-6-P, glutamine, acetyl-CoA and uridine triphosphate (UTP). UDP-GlcNAc is added or removed from serine and threonine residues by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), respectively (73). O-GlcNAcylation plays a role in regulation of glucose metabolism, for instance by regulating gluconeogenic transcription factors forkhead box O1 (FOXO1) and PGC-1α (74,75). In addition, O-GlcNAcylation is important in hepatic glucose sensing, as it activates ChREBP (38). The biology of O-GlcNAcylation is largely unexplored and exact molecular mechanisms and subsequent physiological functions are still unknown.
Interactions between glucose and other metabolic pathways
Glucose sensing is essential for an adequate regulation of its own metabolism in order to maintain glycemia. Importantly, glucose also signals to other metabolic pathways
via both substrate availability and transcriptional regulation by ChREBP. A series of
metabolic processes that closely interact with glucose metabolism are those involved in hepatic lipid metabolism. Glucose metabolites activate ChREBP, which is involved in regulation of the expression of genes involved in de novo lipogenesis and VLDL assembly. Circumstantial evidence suggests that glucose signaling also impacts hepatic bile acid metabolism (76–82), although the exact mechanisms remain to be investigated.
Hepatic fatty acid metabolism
The liver plays a central role in fat homeostasis via de novo lipogenesis, as well as fatty acid uptake, storage, catabolism, and lipid secretion (83) (Fig. 2). In the postprandial state, dietary fatty acids are taken up by the intestine, assembled into chylomicrons and transported to the circulation via the lymphatic system. Lipoprotein lipase (LPL) mediates hydrolysis of chylomicron-associated triglycerides (TGs), which subsequently enter the liver via fatty acid transporters FATP4 and FATP5 and CD36 (83–86). CD36 is a fatty acid translocase that is expressed in heart, skeletal muscle, adipose tissue and by hepatic resident macrophages (Kupffer cells). Although its hepatic expression is very low, mRNA levels positively correlate with liver TG content in rats with hepatic steatosis (87) and patients with non-alcoholic fatty liver disease (NAFLD) exhibit higher CD36 protein levels (88). In mice, CD36 protein levels were shown to be increased in response to high fat diet and to contribute to hepatic fatty acid uptake and dyslipidemia (89). CD36 is a gene target of the lipogenic transcription factors LXR, PXR, and PPARγ, indicating that CD36 plays a role in the development and promotion of hepatic steatosis (88,90).
In addition to hepatic uptake, fatty acids can also be synthesized from excess glucose in the liver. De novo lipogenesis starts with the conversion of acetyl-CoA into malonyl-CoA, which, together with co-factor NADPH, is used as precursor for the synthesis of palmitic acid (C16:0). C16:0 synthesis from acetyl-CoA is catalyzed by ACC1 and FASN. Next, C16:0 is elongated by, amongst others, ELOVL6, to generate long chain fatty acids (LCFAs), which can subsequently be desaturated to form mono- and poly-unsaturated LCFAs by stearoyl-CoA desaturase-1 (SCD1). Importantly, glucose-sensitive transcription factor ChREBP induces the expression of lipogenic enzymes ACC1, FASN, ELOVL6 and SCD1, thus promoting lipogenesis upon activation by
Adipose tissue Acetyl- CoA Glycolysis FATP4/5 CD36 NEFA De novo lipogenesis TG Storage TG Uptake VLDL-TG VLDL secretion β-oxidation Ketone bodies NEFA Lipolysis PL Biliary PL excretion Chylomicrons Figure 2. Schematic overview of hepatic fatty acid metabolism. FATP4/5, fatty acid transporter 4/5; NEFA, non-esterified fatty acids; TG, triglycerides; PL, phospholipids; VLDL, very low-density lipoprotein
Figure 2. Schematic overview of hepatic fatty acid metabolism. FATP4/5, fatty acid transporter
4/5; NEFA, non-esterified fatty acids; TG, triglycerides; PL, phospholipids; VLDL, very low-density lipoprotein.
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glycolytic metabolites. On the other hand, in vitro ChREBP inhibition in primarymouse hepatocytes showed that ChREBP is required for the induction of glycolytic and lipogenic genes in response to glucose (22). Moreover, similar results were demonstrated in ChREBP knockout mice where ChREBP was shown to be required for the lipogenic response to a high-carbohydrate diet (56).
Newly synthesized fatty acids are subsequently esterified with G3P to form TGs, which can be either stored in lipid droplets, or secreted into the circulation as TG-rich VLDL particles. Under normal conditions, only a small amount of TGs is stored in the liver and the majority of TGs are packaged into VLDL particles. Assembly of VLDL starts in the lumen of the ER with the lipidation of a single apolipoprotein B 100 (apoB100) molecule by MTTP (91) and transmembrane 6 superfamily 2 (TM6SF2) (92). Next, additional TGs are packed into the nascent apoB100-containing particle when it travels from the ER to the Golgi, to form VLDL particles which are secreted into the circulation for energy supply to peripheral organs and energy storage in adipose tissue (93).
Fatty acids are also excreted from the liver via the bile. Bile contains mixed micelles, consisting of bile acids, phospholipids – mainly phosphatidylcholine (PC) – and cholesterol. Phospholipids are composed of a phosphate head group and two fatty acids (94). Biliary PC mostly contains palmitate, stearate, oleic acid, linoleic acid or arachidonic acid (95,96). Its secretion is influenced by biliary bile acid concentration, bile acid composition, biliary concentration of hydrophilic organic anions, and the exposure time of the bile acids to the bile canalicular membrane (95,97–102). Overall, hydrophobic bile acids are more potent enhancers of biliary phospholipid secretion as compared to hydrophilic ones (97,99,100). Once in the bile canalicular lumen, biliary phospholipids and bile acids together form mixed micelles to solubilize cholesterol and dietary lipids upon arrival in the intestinal lumen.
In the post-absorptive state, low insulin-to-glucagon ratios promote non-esterified fatty acids (NEFAs) release from the adipose tissue by triacylglycerol lipase and hormone-sensitive lipase (HSL). These NEFAs are secreted into the circulation to enable their use as energy substrate by for instance heart, skeletal muscle, and liver, hence contributing to ‘glucose sparing’ under these conditions. After uptake by the liver via FATP4 and FATP5 and CD36, fatty acids can undergo β-oxidation resulting in the production of acetyl-CoA, FADH2 and NADPH. Co-enzymes FADH2 and NADH are used in the electron transport chain to produce ATP. Part of the acetyl-CoA generated via β-oxidation is used to produce ketone bodies (β-hydroxybutyrate, acetoacetate, and acetone); which serve as important metabolic fuels. As fatty acids cannot cross the blood-brain barrier, the brain is forced to use ketone bodies as an energy source when blood glucose levels drop. Thus under fasting conditions
particularly the brain relies on ketone bodies for its energy supply. Because of the risk of seizures/coma associated with extremely high ketone body concentration in blood, referred to as ketoacidosis, ketone bodies can only be used as a metabolic fuel for a limited period of time without causing damage.
Hepatic bile acid metabolism
Bile acids facilitate absorption of dietary lipids and fat-soluble vitamins in the intestine, and also act as signaling molecules that control lipid and energy metabolism (103). Synthesis of bile acids from cholesterol is believed to occur exclusively in the liver and comprises multiple biochemical reactions initiated by cholesterol 7α-hydroxylase (CYP7A1), the rate-controlling enzyme in the ‘classic’ pathway of primary bile acid synthesis (104). Sterol 12α-hydroxylase (CYP8B1) subsequently generates 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (cholic acid; CA) as end product. As a consequence, hepatic CYP8B1 activity determines the contribution of CA produced in the ‘classic’ pathway relative to 3α,7α-dihydroxy-5β-cholan-24-oic acid (chenodeoxycholic acid; CDCA). CDCA, in contrast to CA, can also be generated via an ‘alternative’ pathway starting with 27-hydroxylation of cholesterol (104). CDCA is efficiently converted to hydrophilic C6-hydroxylated muricholic acids (MCAs) in rodents but not in humans (104). Primary bile acid species are secreted into the intestine where they can be converted by microbial actions to secondary bile acids with distinct physicochemical properties (104) that determine their efficacy to promote fat and cholesterol absorption as well as their signaling functions (103). By signaling through two major receptor pathways; i.e., farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5, also known as G Protein-Coupled Bile Acid Receptor 1; GPBAR1), bile acids act as ‘hormones’ that control hepatic glucose and lipid metabolism (103,105,106). Bile acid-induced FXR activation interferes with glucose metabolism by inhibiting glycolysis through L-PK expression (48). Moreover, FXR interacts with glucose-sensitive transcription factor ChREBP to modulate its activity (48,107). In the liver, TGR5 is expressed in Kupffer cells and sinusoidal endothelial cells (108). Intestinal TGR5 activation stimulates secretion of GLP-1, which in turn enhances insulin secretion from pancreatic β-cells and subsequently stimulates glucose uptake by various organs (109,110).
In mice, FXR regulates hepatic and plasma lipid levels by interfering with de novo lipogenesis via the transcription factor sterol regulatory element binding protein (SREBP-1c) (111). SREBP-1c induces the transcription of ACC1, FASN, and SCD1 (112). Bile acid- or pharmacological ligand-induced FXR activation reduces hepatic SREBP-1c expression via small heterodimer protein (SHP; NR0B2), resulting in reduced hepatic triglyceride levels (111). Moreover, FXR activation lowers plasma triglyceride levels by improving VLDL-TG catabolism, presumably by induction of
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apolipoprotein C2 (apoC2), an established FXR target and activator of lipoproteinlipase (113). Thus, bile acids not only facilitate dietary fat absorption, but also regulate glucose and lipid metabolism via FXR and TGR5 activation.
Metabolic consequences of disturbed hepatic glucose sensing in human
diseases
Dysregulation of hepatic glucose sensing has consequences for glycemia as well as for hepatic glucose- and lipid metabolism. Chronically activated glucose-sensitive transcription factors may contribute to the development and pathophysiology of diseases with abnormal glucose sensing, such as type 2 diabetes and glycogen storage disease type Ia.
Type 2 diabetes
Type 2 diabetes is an age-related disease with an increasing prevalence of 10% of the total population, and is characterized by a decrease in pancreatic β-cell mass and -function (114). Fasting plasma glucose levels subsequently rise, which is compensated for by increased insulin secretion to maintain normoglycemia. High insulin levels and insulin resistance in type 2 diabetes (T2D) are thus generally associated with hyperglycemic episodes and enhanced intrahepatic glucose metabolism (10,115), leading to sustained activation of hepatic glucose sensors (81,116,117). Dysregulation of glycemia in T2D results in hepatic TG accumulation, referred to as hepatic steatosis (118), and is associated with cardiovascular disease and non-alcoholic steatohepatitis (NASH) (119). Several studies investigated the role of glucose-sensitive transcription factor ChREBP in the pathophysiology of dysregulated glycemia and insulin resistance. In ob/ob mice, sustained ChREBP activation results in increased gluconeogenesis, enhanced lipogenesis, and hepatic TG accumulation (118). On the other hand, liver-specific inhibition of ChREBP in ob/ob mice improved hyperlipidemia, hyperglycemia, and hyperinsulinemia (24,118). In T2D patients, increased hepatic ChREBP expression associates with hepatic steatosis and insulin resistance (116).
Besides the signaling effects of bile acids on glucose and lipid metabolism, disturbed glucose homeostasis in T2D is also associated with an increase in 12-hydroxylated bile acids (80–82). In vitro studies have shown that both insulin and glucose induce the expression of CYP7A1 (76,120), while insulin suppresses and glucose induces the expression of CYP8B1 (76,121). The insulin sensitive transcription factor FOXO1 induces the suppression of CYP8B1 (81) and under insulin-resistant conditions, constitutive FOXO1 activation shifts the composition of the bile acid pool towards an increased contribution of CA and its hydrophobic microbial metabolite deoxycholic acid (DCA) (81). Insulin resistance is therefore associated with an increase in CA synthesis (80–82,122), a more hydrophobic bile acid pool in humans (80), as well as
an increase in total plasma bile acid levels (80,122,123).
Changes in bile acid levels and -composition associated with insulin resistance may alter the activation of FXR and/or TGR5. Besides, a more hydrophobic bile acid pool promotes the absorption of dietary cholesterol and fat (124,125). On the other hand, treatment with bile acids or synthetic FXR agonists improves glycemic control (126) and bile acid sequestrants are used as glucose- and lipid lowering drugs in T2D patients (127). Obeticholic acid (OCA), a synthetic bile acid derivative, is a potent FXR agonist and improves insulin sensitivity in rats with hepatic steatosis (128). Overall, bile acid metabolism is an attractive therapeutic target for type 2 diabetes and NAFLD (122).
Glycogen storage disease type I
Glycogen storage diseases (GSDs) represent a group of ultra-rare inherited metabolic disorders of carbohydrate metabolism, caused by enzyme deficiencies in glucose transport, glycogen synthesis, glycogen breakdown or glycolysis (129). The 12 types of GSDs, with an overall incidence of 1 in 20,000 to 43,000 live births, are characterized by the accumulation G6P and/or glycogen in different tissues, with mainly liver, heart and muscles affected (130). Glycogen Storage Disease type 1 (GSD I; Von Gierke disease) has an incidence of 1:100,000 and is caused by mutations in the catalytic subunit (G6PC) of the glucose-6-phophatase (G6Pase) complex (GSD Ia) or in the glucose-6-phosphate transporter SLC37A4 (G6PT) (GSD Ib) (131–133). It is characterized by G6P and glycogen accumulation in liver, kidney and intestine. Because of impaired G6Pase activity in hepatocytes, disturbed glucose metabolism in GSD I results in constitutive activation of hepatic glucose sensors and development of fatty liver and dyslipidemia, similar to T2D (134). In contrast to T2D, blood glucose and insulin levels are low, while, similar to T2D, intrahepatic glucose (G6P) and glycogen levels are high (1,10,135,136). This unique feature of GSD makes it a unique model disease to selectively investigate the pathophysiological consequences of enhanced intrahepatic glucose signaling, independent of insulin.
As the hydrolysis of G6P by G6PC is essential for glucose production, GSD Ia patients present with severe fasting hypoglycemia, which can occur as early as 2-3 hours after a meal. During infancy, perturbed glucose homeostasis leads to failure to thrive and hepatomegaly. Biochemically, patients display hypoglycemia, hyperlipidemia, hyperlactatemia and hyperuricemia. To prevent hypoglycemia, patients have to adhere to a strict diet with frequent intake of uncooked cornstarch and/or nasogastric tube feeding (137,138). Although dietary adherence generally reduces hypoglycemic episodes and largely corrects secondary metabolic derangements, long-term complications of GSD Ia still frequently occur (137–139). Among these complications are nephropathy, osteopenia and osteoporosis, severe hepatic steatosis
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and the development of liver adenomas in young adulthood. GSD Ib patients showsimilar symptoms and complications as compared to GSD Ia, and furthermore develop neutropenia and neutrophil dysfunction over time (137,140–142).
Hypertriglyceridemia and hepatic steatosis in GSD Ia are commonly attributed to an increase in hepatic fatty acid synthesis (143,144). In clinical practice, serum triglyceride levels are considered the most reliable marker for metabolic control in GSD Ia patients (138,145). Moreover, hypertriglyceridemia and poor metabolic control are associated with long-term complications such as liver adenoma progression (146–148). Yet, it is unknown what the mechanistic link is between glycemic control and pathophysiological mechanisms that underlie symptoms and complications. Understanding of the relationship between metabolic control and hyperlipidemia is of great importance to further improve and personalize GSD Ia patient care. Investigation of disease mechanisms of GSD I and its consequences is however challenging because of the limited number of patients and the inaccessibility of organs involved.
Scope and outline of this thesis
The studies described in this thesis address the (patho)physiological consequences of excessive hepatic glucose signaling in GSD Ia. The work focuses on the effects of disturbed glucose sensing on lipid and bile acid metabolism, the contribution of hepatic ChREBP to GSD Ia-associated NAFLD development, and the therapeutic potential of FXR activators to reduce NAFLD in GSD Ia. It is commonly assumed that hepatic steatosis and hypertriglyceridemia in GSD Ia result from an increase in hepatic
de novo lipogenesis and VLDL secretion driven by the prevailing high glycolytic flux,
but the exact mechanisms linking circulating glycemia and hyperlipidemia in GSD
Blood glucose G6PC G6PT L-G6pc -/-S4048 G6P Glycogen TG TCA cycle VLDL Citrate
Figure 3. Hepatocyte specific G6PC knockout (L-G6pc-/-) mice and mice receiving the pharmacological
G6PT inhibitor S4048 are used in this thesis to study altered lipid and bile metabolism in GSD Ia.
Figure 3. Hepatocyte specific G6PC knockout (L-G6pc-/-) mice and mice receiving the pharmacological
G6PT inhibitor S4048 are used in this thesis to study altered lipid and bile metabolism in GSD Ia. G6PC, glucose-6-phosphatase; G6PT, glucose-6-phosphate transporter; G6P, glucose-6-phosphate;
Ia are unknown. Moreover, it is as yet not well understood to what extent enhanced glycolysis and de novo lipogenesis contribute to fatty liver in GSD Ia. Regarding bile acid metabolism, it has been shown that insulin resistance shifts the composition of the bile acid pool towards more CA. However, a direct regulatory role of intrahepatic glucose on bile acid synthesis and the physiological consequences thereof have yet remained elusive.
GSD Ia is characterized by a strong accumulation of G6P inside hepatocytes and, importantly, low fasting glucose and insulin levels. In this thesis, we take advantage of this unique feature to evaluate the effects of intracellular glucose versus blood glucose and insulin and, hence, to selectively establish the effects of intra- versus extrahepatic glucose signaling on lipid and bile acid metabolism. Although deviations in blood glucose are opposite in GSD Ia and diabetes, intrahepatic glucose is enhanced in both diseases and the hepatic phenotypes are very similar, rendering GSD Ia as a ‘model’ for diabetic liver disease. Investigation of (patho)physiological consequences of excessive intrahepatic glucose signaling in the rare metabolic disorder GSD Ia can thus provide insight in metabolic disturbances in more common diseases coinciding with enhanced glucose signaling, like type 2 diabetes. To this end, we use hepatocyte specific G6PC knockout (L-G6pc-/-) mice and mice that receive the pharmacological
G6PT inhibitor S4048 (149,150) (Fig. 3), combined with innovative techniques to quantify metabolic fluxes in vivo. Besides the fact that two different components of the G6Pase complex are affected, i.e., respectively G6PC1 and G6PT, these mouse models allow us to differentiate between ‘chronic’ and ‘acute’ GSD I states. Although the timeframe of disease introduction and -progression are different between these two models, both present fasting hypoglycemia, hyperlipidemia, hepatomegaly, and hepatic steatosis at the time of sacrifice, resembling symptoms and complications observed in GSD I patients.
The studies described in this thesis aim to investigate 1) the physiological mechanisms contributing to fatty liver disease and hyperlipidemia in GSD Ia and 2) the contribution of enhanced glycolysis and de novo lipogenesis to fatty liver disease in GSD Ia and 3) the independent role of glucose to regulate hepatic bile acid metabolism.
To establish the link between glycemia and hypertriglyceridemia in GSD Ia, we performed in chapter 2 a systematic analysis of whole-body TG metabolism in normo- and hypoglycemic GSD Ia mice. In chapter 3 we assessed the contribution of ChREBP to the development of fatty liver in a GSD Ia mouse model. Chapter 4 describes the effects of pharmacological FXR activation on lipid metabolism in GSD Ia. In chapter 5 we investigated the regulatory role of intrahepatic glucose on bile acid synthesis and the signaling cascade involved. Finally, in chapter 6 we discuss the findings described in this thesis and put them in a broader (clinical) perspective.
1
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