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 Discussion
Dysregulation of hepatic glucose sensing induces several serious metabolic responses that adversely affect health. The studies described in this thesis have been focused on the (patho)physiological consequences of constitutively active hepatic glucose signaling as occurs in Glycogen Storage Disease type 1a (GSD Ia). GSD Ia is characterized by intracellular accumulation of glucose-6-phosphate (G6P, the first intracellular metabolite of glucose) in hepatocytes while fasting blood glucose and insulin levels are low. In the work presented, we took advantage of this unique feature of GSD Ia to selectively establish effects of increased intrahepatic glucose sensing on several metabolic processes in the liver. Importantly, GSD Ia provides a ‘model’ for diabetic liver disease (1,2), a major global health problem. Although deviations in blood glucose are opposite in GSD Ia and type 2 diabetes (low versus high blood glucose), intrahepatic glucose metabolism is enhanced in both conditions. Moreover, the hepatic consequences of GSD Ia and type 2 diabetes are very similar and encompass a high glycolytic rate, cellular glycogen and lipid accumulation as well as an increased risk for liver tumor development (1,3–7).
Aims of the work presented in this thesis were to establish 1) the physiological mechanisms contributing to fatty liver disease and hyperlipidemia in GSD Ia; 2) the contribution of enhanced glycolysis and de novo lipogenesis to fatty liver disease in GSD Ia; and 3) the independent regulatory role of glucose in the control of hepatic bile acid synthesis. The findings obtained contribute to a better understanding of the often overlooked contribution of enhanced intrahepatic glucose metabolism, independent of prevailing blood glucose and insulin concentrations, to the development and progression of NAFLD and hyperlipidemia in GSD Ia. Importantly, the studies described in this thesis may also contribute to novel strategies to treat type 2 diabetes complications. Figure 1 gives an overview of the main findings described in this thesis.
Advantages and limitations of the GSD Ia mouse model used
Application of a hepatocyte-specific G6pc knockout mouse model allowed to specifically investigate the pathophysiological consequences of enhanced hepatic glucose signaling in GSD Ia. The ability to induce G6Pase-deficiency at any age desired offers several advantages over use of “conventional” knockout or liver-specific knockout mice. In the studies reported in this thesis, consequences of enhanced hepatic glucose signaling were investigated in adult mice with a fully developed liver. In the first weeks of life, activation of endogenous glucose production by the liver is critical because of the low glucose content in milk, leading to adaptations of glucose and fatty acid metabolism (8). Using adult mice, we were able to investigate the consequences of enhanced hepatic glucose signaling in a developed liver adapted to the prevailing metabolic conditions. Moreover, this model allowed defining the exact time of exposure to excessive hepatic glucose signaling. It should be noted that there
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are some limitations associated with the use this mouse model and that diff erencesbetween preclinical fi ndings reported in this thesis and those from studies in GSD Ia patients do exist. From a translational point of view, one should fi rst take into account that a hepatocyte-specifi c rather than a whole body G6pc knockout mouse model (9–11) was used. Whole body G6pc knockout mouse models cannot be used to investigate long-term complications as they rarely survive over 3 months of age, unless gene therapy is performed (12). In addition, whole body G6pc knockout mice require intraperitoneal glucose injections to prevent seizures (13). Indeed, G6pc is also expressed in kidney and intestine, and in contrast to hepatocyte-specifi c G6pc knockout mice (13), GSD Ia patients suff er also from kidney failure and infl ammatory bowel disease (12). During prolonged fasting, kidney cells and enterocytes likely contribute to residual glucose production in our mouse model (14,15). Second, hepatic G6pc deletion was induced during adulthood and for only 10 days until sacrifi ce, which may mask potential metabolic derangements and fl uxes occurring over longer periods of time. Moreover, G6pc deletion during adulthood does not aff ect liver development, as it will do in GSD Ia patients who are G6pc defi cient from birth onwards. Despite these limitations, the mouse model used does present with fasting hypoglycemia, hyperlipidemia, hepatomegaly, and hepatic steatosis, i.e., all hepatocyte-borne symptoms and complications observed in GSD I patients and thus render the hepatocyte-specifi c G6pc knockout mouse as a highly valuable pre-clinical model for GSD Ia.
Figure 1. Schematic overview of the main fi ndings described in this thesis regarding the (patho)physiological consequences of constitutively active hepatic glucose signalling in GSD Ia. GCK, glucokinase; G6PC, glucose-6-phosphatase; G6P, glucose-6-phosphate; TG, triglycerides;
VLDL, very low-density lipoproteins; LDL, low-density lipoproteins; NEFA, non-esterifi ed fatty acids; ChREBP, carbohydrate response element binding protein; LPL, lipoprotein lipase; HL, hepatic lipase;
Cyp7a1, cholesterol 7α-hydroxylase; Cyp8b1, sterol 12α-hydroxylase, Cyp27a1, sterol 27-hydroxylase, Cyp7b1, oxysterol 7α-hydroxylase.
Glycemia and VLDL-TG metabolism
In clinical practice plasma triglyceride (TG) concentrations are currently regarded as most important biomarker for metabolic control in GSD Ia patients (16,17), although the mechanistic link between hyperlipidemia and disturbed glycemia is poorly understood. In this thesis, it is shown that blood glucose levels affect VLDL-TG catabolism (chapter 2), the origins of fatty liver (chapter 2), as well as bile acid metabolism (chapter 5), and that disturbed glycemia contributes to the hepatic GSD Ia phenotype.
Chapter 2 addresses the physiological mechanisms that link glycemic state to
hyperlipidemia by performing a systemic analysis of whole-body TG metabolism in normo- and hypoglycemic L-G6pc-/- mice. A concomitant increase in VLDL-TG production and decrease in VLDL-VLDL-TG catabolism in fasted, but not in fed L-G6pc-/- mice revealed, for the first time, a direct link between hypoglycemia and hypertriglyceridemia. Published data obtained in human GSD Ia patients suggested that altered VLDL production may contribute to the severity of hypertriglyceridemia in GSD Ia, although these results are not consistent (18,19). The data presented in
chapter 2 suggest that the amount of VLDL particles secreted by the liver remains
(largely) unaffected in L-G6pc-/- mice. Consequently, since each VLDL particle contains a single apolipoprotein B (apoB) molecule, assessment of apoB turnover rates alone, as commonly performed (20–23), is not sufficient to establish the cause(s) of altered VLDL-TG production in GSD Ia. Data in L-G6pc-/- mice show that lipidation of apoB and thus the amount of TG per VLDL was increased, resulting in the production of larger VLDL particles by the liver. Our findings indicate that, like in L-G6pc-/- mice, excess TGs of GSD Ia patients are almost exclusively associated with VLDLs. Analysis of the amount of TGs per apoB molecule in plasma of GSD Ia patients may therefore provide a more reliable indicator of the origin of hypertriglyceridemia in GSD Ia. Studies described in chapter 2 also show that hypoglycemia inhibits VLDL catabolism in L-G6pc-/- mice. Activities of lipoprotein lipase (LPL) and hepatic lipase (HL) are regulated by apolipoproteins and angiopoietin-like proteins (20–23). It has been reported that the apoC2/C3 ratio (24–27) is reduced in VLDL particles of GSD Ia patients, which may contribute to reduced LPL activity in these patients (20). In addition to LPL regulators Angptl3, 6, and 8 (28), Angptl4 is an established inhibitor of both HL and LPL activity (29,30). However, altered expression of angiopoietin-like proteins nor changes in apoC2/C3 ratio in fasted L-G6pc-/- mice were observed. Instead, the data suggest that the activities of LPL and/or HL were reduced by a factor that is specifically altered under fasted, hypoglycemic conditions. Non-esterified fatty acids (NEFAs), and especially oleate as one of the most prevalent NEFAs, are able to inhibit LPL activity (26) and NEFAs appeared to be elevated in hypoglycemic L-G6pc-/- mice. We propose that increased NEFAs/oleate levels in fasted L-G6pc
-/-6
mice may contribute to impaired VLDL catabolism. Impaired VLDL catabolism haspreviously been suggested to contribute to hyperlipidemia in normoglycemic GSD Ia patients (31–41). No data is available for hypoglycemic GSD I patients, as GSD I patients are generally kept in a semi-fed state. However, as adipocyte lipolysis (20,22,31,42–44), circulating total NEFAs and oleate levels were shown to be increased in normoglycemic GSD Ia patients, we hypothesize that these fatty acids arrest VLDL catabolism, leading to hypertriglyceridemia, and that these effects will be even more marked in those patients that show a poor metabolic control.
Factors that might contribute to impaired VLDL-TG catabolism by increased NEFAs in GSD Ia are elevated glucagon and glucocorticoid levels (45). Glucagon levels are directly responsive to glycemia and glucagon is a well-established enhancer of adipose tissue lipolysis via cAMP signaling (1,46,47). The significantly increased glucagon levels in hypoglycemic L-G6pc-/- mice potentially contributed to enhanced adipose tissue lipolysis and increased NEFAs (chapter 2). Glucocorticoids, mainly cortisol in humans and corticosterone in rodents, increase during fasting, stimulate adipocyte lipolysis (48), and promote VLDL production and secretion (49) by inducing hepatic ACC and FASN transcription, promoting VLDL assembly (50,51), and reducing APOB degradation (51–53). A direct inhibitory effect of glucocorticoids on LPL activity is unknown, but glucocorticoids can inhibit clearance of TG-rich lipoproteins by the liver via miR-379-mediated inhibition of LDLR expression (54). Hepatic uptake of labelled VLDL-like particles was slightly reduced in L-G6pc -/-mice, however it was not affected by the glycemic state (chapter 2). Moreover, as glucocorticoids stimulate lipolysis, they also contribute to impaired VLDL-TG catabolism by increasing NEFA and particularly circulating oleate levels. Although further research is needed into the exact cause of impaired VLDL-TG catabolism, it can be speculated that elevated glucocorticoid signaling may contribute to hampered VLDL-TG catabolism in hypoglycemic GSD Ia.
Glycemia and hepatic triglyceride accumulation
Dyslipidemia in GSD Ia patients, i.e. the presence of both hypertriglyceridemia and NAFLD, is commonly attributed to increased hepatic fatty acid synthesis (55). The contribution of de novo lipogenesis to hepatic lipid accumulation in L-G6pc-/- mice was assessed in chapter 2, 3 and 4 using a sodium [1-13C]-acetate solution supplied
via the drinking water for 48 hours. Contribution of de novo synthesis, as quantified
by a mass isotopomer distribution analysis (MIDA) approach, typically accounted for up to 20% of total hepatic fat content, a value comparable to that observed in healthy humans in the postprandial state (22,23). De novo lipogenesis in humans is usually determined by labeled water (2H2O, or deuterated water) (56) incorporation, which results in similar fractional fatty acid synthesis rates as compared to[1-13C]-acetate, but is rather inexpensive and hence better applicable for long-term studies
(57–59). Prolonged labeling of the acetyl-CoA pool (>48h) would presumably lead to an increased contribution of L-G6pc-/- lipogenesis (56,60). In a human study, administration of deuterated water for 3 to 5-weeks showed that de novo lipogenesis contributed for 11% up to 38.5% to the intrahepatic triglyceride content in lean and obese-NAFLD individuals, respectively (61). The data obtained in our studies with labeled acetate indicate that fatty liver in GSD Ia mice is not solely caused by an increase in de novo fatty acid synthesis, as this only maximally accounts for ~20% of liver fat. We therefore propose that storage of pre-existing ‘old fat’ has a major contribution to fatty liver disease in GSD Ia. Chapter 2 reveals an intriguing difference in the origin of hepatic steatosis in normo- versus hypoglycemic L-G6pc-/- mice. Hepatic de novo fatty acid synthesis mainly contributed to hepatic lipid accumulation in fed
L-G6pc-/- mice, while in fasted L-G6pc-/- mice liver steatosis was mainly associated with enhanced adipose tissue lipolysis and hepatic fatty acid elongation. Glycemia thus (partly) determines the source of fatty acids that accumulate in the liver in L-G6pc-/- mice. Similar to what we found in fed L-G6pc-/- mice, de novo lipogenesis is increased in GSD Ia patients (22,23), but it was shown that it could only contribute for a minor part to hepatic steatosis (23). Bandsma et al. suggested that the hepatic influx of NEFAs may be the major contributor to fatty liver disease in GSD I (62). Indeed, we found that in fasted L-G6cp-/- mice enhanced adipose tissue lipolysis and subsequent uptake and elongation of fatty acids released by the adipose tissue were the most predominant cause of fatty liver, showing that hepatic steatosis occurs not solely due to enhanced de novo lipogenesis, but that enhanced NEFA influx is also a major contributor.
Intra- versus extrahepatic glucose signaling and bile acid metabolism
The study described in chapter 5 identified a novel link between hepatic glucose signaling and bile acid metabolism. Previously, it was show that insulin resistance is associated with an increase in cholic acid synthesis relative to that of chenodeoxycholic acid. This is generally attributed to constitutive activation of Forkhead box protein O1 (FOXO1) and subsequent induction of CYP8B1, the enzyme that catalyzes the crucial 12α hydroxylation reaction in cholic acid synthesis (63,64). Increased contribution of cholic acid and its metabolite deoxycholic acid result in a more hydrophobic bile acid pool in insulin resistant subjects (65–67). Insulin resistance is generally associated with hyperglycemic episodes, enhancing intrahepatic glucose metabolism similar to GSD I (65). In GSD Ia mice, hepatic accumulation of G6P resulted in ChREBP-mediated induction of Cyp8b1 and subsequent induction of cholic acid synthesis. Intrahepatic glucose thus regulates the expression of Cyp8b1, independent of insulin. As a consequence, G6P-ChREBP signaling increases the relative abundance of cholic acid-derived bile acids, resulting in a more hydrophobic bile acid pool in mice. A shift in the hydrophobicity of the bile acid pool changes the capacity for intestinal lipid solubilization and uptake (68–70). In L-G6pc-/- mice, the G6P-induced increase
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in Cyp8b1 expression resulted in a more hydrophobic bile acid composition, whichwas consistent with a reduction in fecal neutral sterol excretion compatible with enhanced intestinal cholesterol absorption. Thus, via hepatic ChREBP-CYP8B1 signaling, intracellular glucose controls bile acid synthesis and intestinal cholesterol handling. This signaling cascade likely contributes to altered bile acid metabolism and its (patho)physiological consequences, such as altered cholesterol absorption, in conditions coinciding with excessive intrahepatic glucose signaling such as GSD I and type 2 diabetes. A major difference in bile acid metabolism between mice and humans is the presence of very hydrophilic muricholic acids in murine bile (71). The human bile acid pool is more hydrophobic as compared to mice, due to the lack of the muricholic acid-producing enzyme CYP2C70 that is specific to mice and rats (72). In humans, G6P-mediated CYP8B1 induction promotes cholic acid synthesis at the expense of dihydroxylated chenodeoxycholic acid, resulting in a more hydrophilic, rather than a more hydrophobic bile acid pool, with a potentially opposite effect on intestinal cholesterol absorption. Similar changes in the bile acid pool are seen in diabetic and insulin resistant subjects (65,67). There are no reports focusing on disturbed bile acid metabolism and the consequences for intestinal cholesterol absorption in GDS Ia patients. With respect to hypercholesterolemia in GSD Ia, future studies are needed to establish the impact of intrahepatic G6P-CYP8B1 signaling on bile acid synthesis, pool size and composition and on intestinal cholesterol absorption.
Hepatic expression levels of CYP7A1, the rate-controlling enzyme of primary bile acid synthesis (cholic acids and chenodeoxycholic acids), were decreased in hypoglycemic, but not in normoglycemic, L-G6pc-/- mice (chapter 5). Hyperglycemia, on the other hand, has been shown to induce hepatic Cyp7a1 gene expression (73,74). Circulating glucose levels and consequent changes in insulin and glucagon concentrations are major postprandial factors to regulate CYP7A1 protein levels (74). CYP7A1 protein levels and bile acid synthesis follow a circadian rhythm that is in phase with the feeding-fasting cycle (75–78). Increased production of bile acids in response to elevated blood glucose levels will facilitate intestinal fat absorption. At the same time, bile acid-mediated activation of TGR5 stimulates secretion of GLP-1 and subsequent pancreatic insulin secretion, to facilitate glucose uptake by various organs (79). Thus, attenuation of CYP7A1 expression by glycemia through insulin and glucagon, independent of hepatic G6P signaling, likely contributes to the circadian rhythm of bile acid synthesis.
Glucose sensing via the hepatic G6P-ChREBP axis, the role of
posttranslational modifications
Carbohydrate response element binding protein (ChREBP) is a key glucose-sensitive transcription factor that is activated in GSD Ia and Ib, and which mediates the
induction of glycolytic and lipogenic genes in GSD Ib (28,80). The results in chapter 3 confirm that ChREBP indeed fulfills a similar role in GSD Ia. Moreover, it was found that enhanced hepatic ChREBP activity limits hepatomegaly, hepatocyte vacuolation, and NAFLD development in GSD Ia, illustrating the protective role of ChREBP-dependent glucose sensing under these conditions. ChREBP is activated by glycolytic metabolites, such as glucose-6-phosphate (G6P) – a cross-road molecule in glucose metabolism – and the PPP intermediate xylulose-5-phosphate. Upon activation, ChREBP induces hepatic glycolytic and lipogenic pathways via transcriptional activation. It was recently shown that, next to acetylation (81), also O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) increases the transcriptional activity of ChREBP on lipogenic promoters (82,83). Host cell factor 1 (HCF-1) interacts with ChREBP to stimulate its O-GlcNAcylation and activation, resulting in glucose-dependent epigenetic regulation of lipogenic gene promoters (83).
The potential role of ChREBP to mediate posttranscriptional modification upon enhanced glucose signaling, however, is largely unexplored. ChREBP is a key determinant of glycolysis and a direct transcriptional regulator of ATP-citrate lyase (ACLY), the essential enzyme for glucose-induced histone acetylation (84,85). Enhanced ChREBP activity thus leads to formation of glucose-derived citrate and subsequent acetyl-CoA production, the latter representing the substrate for (histone) acetylation. Based on the findings in chapter 5, we propose that ChREBP induces Cyp8b1 expression upon cellular glucose signaling via a posttranscriptional mechanism, i.e. via histone 4 acetylation dynamics. Previously, it was shown that histone acetylation increases ChREBP-ChoRE binding at the fatty acid synthase (FASN) promoter in vitro (86). ChREBP-mediated interference with histone modifications were proposed to be crucial for the enhanced transcription of FASN, as it resulted in an active chromatin structure increasing FASN transcription upon high glucose. Our findings show that the regulatory role of ChREBP upon G6P-mediated activation is not limited to enhanced transcription of its target genes by binding to a ChoRE in the promoter region, but may also involve glucose-induced posttranscriptional mechanisms to regulate the expression of genes such as Cyp8b1. ChREBP is also known to physically interact with transcription factor HNF4α and to modulate its binding to the promoters of FASN, LPK, and ChREBPβ (87). Cell reporter assay data in chapter 3 show an additive effect of ChREBPβ/MLX on the HNF4α-mediated activation of the murine Tm6sf2 reporter. Furthermore, ChIP-qPCR analysis under fed and fasted conditions showed an increased recruitment of both ChREBP and HNF4α to the mouse TM6SF2 gene. Our results in chapter
3 suggest that HNF4α contributes to basal transcription of Tm6sf2 in mouse liver,
while ChREBP mediates a glucose/G6P-induced induction. Dedicated molecular studies are needed to reveal whether ChREBP physically interacts with HNF4α
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upon glucose stimulation to promote HNF4α transcriptional activity, resulting in aglucose-mediated induction of Tm6sf2.
Glucose signaling and hepatic adenoma development in GSD I
Depending on the investigated age group, 22%-75% of GSD I patients develop hepatic adenomas in young adulthood (16,17), and adenomas are a main reason for hospitalization in adult patients (4,88–92). The mechanisms behind hepatic adenoma development and the risk for malignant transformation in GSD I are as yet unknown. Enhanced glucose metabolism and activation of glycolysis, glycogen storage, fatty acid synthesis, uric acid, lactate, and nucleotide production might reprogram the GSD Ia liver and generate a favorable tumorigenic environment (4,93). Earlier, it was hypothesized that disturbed fatty acid metabolism induces gene mutations via the generation of hydrogen peroxide (93). It could very well be that cellular stress, like oxidative stress and autophagy deregulation, caused by toxic accumulation of glycogen or TG plays an important role in tumor formation (7,94). Several studies have shown dysfunctional mitochondria in GSD Ia (7,95–97), which might be due to downregulation of SIRT1 (95,98). Moreover, hepatic autophagy is impaired (96), leading to accumulation of damaged mitochondria that generate reactive oxygen species (ROS) (95,97), which can subsequently contribute to oxidative DNA damage (99). In addition, enhanced glycolysis in GSD I might result in increased O-GlcNAcylation, a process that is also upregulated in cancer cells. Although O-GlcNAcylation is not known to initiate tumor development, this process is upregulated in cancer cells and promotes tumorigenesis (100). The substrate for
O-GlcNAcylation, UDP-N-acetylglucosamine (UDP-GlcNAc), is derived from
F-6-P, glutamine, acetyl-CoA and uridine triphosphate (UTP) via the hexosamine biosynthesis pathway (HBP). The HBP is upregulated in hyperglycemia and diabetes (101) and is considered as a nutrient sensing pathway, as it depends on the major metabolic pathways in a cell, i.e. glucose metabolism, amino acid metabolism, fatty acid metabolism and nucleotide metabolism. Because G6P is a precursor for F-6-P, acetyl-CoA and UTP, an enhanced flux through the HBP and a consequent increase in protein O-GlcNAcylation may be expected in GSD I. Although we did not collect evidence for increased UDP-GlcNAc concentrations in livers of L-G6pc-/- mice as compared to controls (data not shown), it cannot be excluded that an increased HBP flux in L-G6pc-/- mice actually occurred, as changes in fluxes do not always translate into altered metabolite concentrations (102). It was suggested that O-GlcNAcylation induces a metabolic shift towards lipid synthesis, favoring proliferation and creating a tumorigenic environment in GSD Ia (96). The role of O-GlcNAcylation in adenoma development in GSD Ia, as well as the mechanistic link between poor metabolic control and liver adenoma progression remains to be investigated.
Consequences of glycemic control for GSD I symptoms and complications
GSD I patients have to adhere to strict dietary management, including frequent meals, continuous nocturnal gastric drip feeding and/or intake of uncooked cornstarch. Although not clearly defined, ‘good metabolic control’ in GSD Ia patients, mostly achieved by strict dietary compliance, prevents hypoglycemia and largely corrects secondary metabolic derangements, such as hyperlactacidemia, hyperuricemia, and hypertriglyceridemia (103). Poor metabolic control and hypertriglyceridemia are associated with increased risk to develop hepatocellular adenomas (16,104–106), osteoporosis (6,107), and renal complications (88,108,109).
The studies described in this thesis reveal how the glycemic state contributes to GSD Ia symptoms by affecting VLDL-TG catabolism (chapter 2), fatty liver development (chapter 2), and bile acid metabolism (chapter 5). Poor metabolic control and hypoglycemic episodes in L-G6pc-/- mice coincide with more severe liver steatosis and hypertriglyceridemia, resulting from enhanced adipose tissue lipolysis and impaired VLDL-TG catabolism. Moreover, blood glucose levels regulate hepatic expression of murine Cyp7a1, the rate-controlling enzyme in bile acid synthesis, and prolonged fasting concomitantly decreases total bile acid pool size (110). Enzymes involved in bile acid synthesis show a circadian rhythm in their hepatic expression and enzyme activities, and Cyp7a1 expression peaks during food intake (111,112). It could therefore be hypothesized that poor metabolic control in GSD Ia, as well as the intake of frequent meals and continuous nocturnal gastric drip feeding, could change the circadian rhythm of bile acid synthesis, thereby affecting nutrient absorption, cholesterol turnover and activities of various bile acid-activated metabolic pathways. Future studies are needed to reveal the consequences of disturbed bile acid metabolism for intestinal cholesterol absorption in GDS Ia patients.
Therapeutic opportunities in GSD I
Gene therapy is the gold standard treatment for monogenetic diseases and also represents a promising treatment for GSD Ia. Correcting hepatic G6pc enzymatic activity to 3-63% of wild type values by AAV-mediated gene therapy maintains glucose homeostasis and prevents development of hepatic adenomas in mice (113). Although the first phase I/II clinical trial in humans to study safety and dosing of an adeno-associated virus serotype 8 (AAV8) with G6PC for liver-directed gene therapy is currently ongoing (ClinicalTrials.gov Identifier NCT03517085), it may still take a considerable amount of time before this therapy reaches the clinic. Importantly, gene therapy will not be available for all patients because of immunity against the viral vector used to deliver the enzyme (114–117). Furthermore, the efficacy in patients still needs to be proven and potential side effects and risks of viral delivery need to be established. Therefore, development of alternative therapeutic strategies is still warranted to reduce or prevent GSD Ia symptoms and complications.
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The potential therapeutic effects of ChREBP inhibition (chapter 3) and FXR activation(chapter 4) were evaluated in the mouse model for GSD Ia. Chapter 2 describes that hepatic ChREBP maintains hepatic TG balance in GSD Ia by concomitantly regulating fatty acid synthesis, fatty acid oxidation, and VLDL-TG secretion. It has been reported that hepatic ChREBP knockdown in a mouse model for diabetes type 2 protects these animals against non-alcoholic fatty liver disease (NAFLD) (80). Although normalization of hepatic ChREBP activity in GSD Ia liver reduced glycolysis, it aggravated hepatomegaly due to further accumulation of glycogen. In addition, ChREBP knockdown decreased VLDL lipidation and –secretion by reducing Mttp and Tm6sf2 expression, resulting in increased fat storage in the liver. It can thus be concluded that enhanced ChREBP activity is actually beneficial in GSD Ia as it limits NAFLD development under these conditions. Because ChREBP-dependent VLDL lipidation is a key determinant of plasma TG levels in GSD Ia, genetic variations in MTTP, TM6SF2, or ChREBP may contribute to the clinical heterogeneity in hyperlipidemia observed in these patients (118,119). This possibility needs to be further investigated.
In view of the reported role of FXR in control of glycolysis and cholesterol- and lipid metabolism, as well as the beneficial effects of pharmacological FXR activation on NAFLD (120,121), it was investigated whether pharmacological FXR activation prevents or delays development of fatty liver disease and hyperlipidemia in GSD Ia (chapter 4). Upon FXR activation, glycolysis was redirected towards gluconeogenesis, which promoted hepatic G6P accumulation and limited the substrate availability for
de novo lipogenesis. Consistent with previous studies in obese or diabetic mouse
models (122–126), it was observed that pharmacological FXR activation led to a slight reduction in hepatic de novo lipogenesis in GSD Ia mice. As concluded in
chapters 2, 3, and 4, de novo lipogenesis has only a minor contribution to fatty liver
disease in GSD Ia, with a maximum of ~20%. Therefore, targeting this pathway may not be sufficient to achieve complete normalization in hepatic TG content. In agreement with this finding, the effects of inhibiting de novo lipogenesis by PX20606 in hepatic GSD Ia were rather modest and did not result in a complete normalization of hepatic TG content. Possibly, the stimulatory signal of G6P-ChREBP on glycolysis and lipogenesis in GSD Ia is stronger than the potential suppressive effect of FXR. Although some studies in rodents show beneficial effects of FXR activation on hepatic lipid content (122,124,125), there is still no proof for inhibition of lipogenesis by activation of FXR in humans and therefore alternative strategies are likely warranted to improve hepatic steatosis. Inhibition of acetyl-coenzyme A carboxylases (ACC1 and ACC2), enzymes critical in de novo fatty acid synthesis and fatty acid oxidation, decreased de novo lipogenesis in overweight adult males (127–129). It can be hypothesized that combined FXR and ACC inhibition may be more effective to prevent fatty liver disease in GSD Ia.
Hepatic steatosis in L-G6pc-/- mice was also shown to be associated with glycemic control and enhanced adipose tissue lipolysis, which potentially also provides a more effective node for intervention. Inhibition of lipolysis might be an attractive tool to lower NEFAs and prevent hepatic steatosis and arrest of VLDL catabolism. Although glucagon receptor antagonists decrease adipose tissue lipolysis and NEFAs, they may actually increase hepatic fat content (130–132). The mechanism by which glucagon receptor antagonists increase steatosis is as yet unknown, but it was suggested that a certain level of glucagon receptor signaling in hepatocytes might be required to maintain or regulate synthesis, secretion and oxidation of lipids (131,132). Glucocorticoid receptor modulators, like CORT118335, might potentially be interesting therapeutics for hepatic steatosis in GSD Ia, as they decrease hepatic fat content via enhanced VLDL production, although plasma cholesterol levels were increased (51). The therapeutic potential of glucocorticoid receptor modulators should be further investigated in GSD Ia. Partial inhibition of lipolysis by Atglistatin, an inhibitor of adipose triglyceride lipase (Atgl), reduced hepatic TG levels by 73% in
ob/ob mice (133), making it an attractive therapeutic treatment to reduce fatty liver
in GSD Ia. However, LPL activity in white adipose tissue in re-fed animals was also lowered by Atglistatin, resulting in a delayed postprandial clearance of chylomicrons (133). It was suggested that Atglistatin-mediated inhibition of adipose tissue lipolysis led to suppression of adipocyte PPARγ target gene expression, causing decreased TG accumulation in white adipose tissue. In GSD Ia, however, Atglistatin may at the same time also worsen the existing hypertriglyceridemia, as hypertriglyceridemia in hypoglycemic L-G6pc-/- mice was associated with arrested VLDL catabolism (chapter
2). It would be worthwhile to study the exact mechanism of VLDL catabolism
in GSD Ia, and the effect of partial inhibition of adipose tissue lipolysis, both on hepatic steatosis and hyperlipidemia. Considering the association between plasma TG levels and long-term complications such as hepatic adenoma development, detailed mechanistic understanding of the factors that link between glycemia and hypertriglyceridemia will potentially contribute to improved and personalized care for GSD Ia patients.
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