Impaired <scp>Very‐Low‐Density Lipoprotein</scp> catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

Hoogerland, Joanne A.; Peeks, Fabian; Hijmans, Brenda S.; Wolters, Justina C.; Kooijman, Sander; Bos, Trijnie; Bleeker, Aycha; Dijk, Theo H. van; Wolters, Henk; Gerding, Albert; Eunen, Karen van; Havinga, Rick; Pronk, Amanda; Rensen, Patrick C.N.; Mithieux, Gilles; Rajas, Fabienne; Kuipers, Folkert; Reijngoud, Dirk-Jan; Derks, Terry G J; Oosterveer, Maaike H.

doi:10.1002/jimd.12380

Cited by 13 publications

(8 citation statements)

References 70 publications

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“…This is of relevance, since in vitro experiments have also shown that SHBG can affect de novo lipogenesis [9]. By studying patients with GSD1a, who are characterized by a primary genetic defect resulting in high intrahepatic glucose-6-phosphate levels and, consequently, higher rates of de novo lipogenesis [11,12,24], our current observations support the concept that de novo lipogenesis results in lower serum SHBG levels in humans. This conclusion, however, deserves some caution given the small, predominantly female population that was studied, which limits the generalisability of the our findings.…”

Section: Discussionsupporting

confidence: 78%

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a

Simons

Valkenburg

Telgenkamp

et al. 2022

J Endocrinol Invest

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Purpose De novo lipogenesis has been inversely associated with serum sex hormone-binding globulin (SHBG) levels. However, the directionality of this association has remained uncertain. We, therefore, studied individuals with glycogen storage disease type 1a (GSD1a), who are characterized by a genetic defect in glucose-6-phosphatase resulting in increased rates of de novo lipogenesis, to assess the downstream effect on serum SHBG levels. Methods A case–control study comparing serum SHBG levels in patients with GSD1a (n = 10) and controls matched for age, sex, and BMI (n = 10). Intrahepatic lipid content and saturated fatty acid fraction were quantified by proton magnetic resonance spectroscopy. Results Serum SHBG levels were statistically significantly lower in patients with GSD1a compared to the controls (p = 0.041), while intrahepatic lipid content and intrahepatic saturated fatty acid fraction—a marker of de novo lipogenesis—were significantly higher in patients with GSD1a (p = 0.001 and p = 0.019, respectively). In addition, there was a statistically significant, inverse association of intrahepatic lipid content and saturated fatty acid fraction with serum SHBG levels in patients and controls combined (β: − 0.28, 95% CI: − 0.47;− 0.09 and β: − 0.02, 95% CI: − 0.04;− 0.01, respectively). Conclusion Patients with GSD1a, who are characterized by genetically determined higher rates of de novo lipogenesis, have lower serum SHBG levels than controls.

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Section: Discussionsupporting

confidence: 78%

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a

Simons

Valkenburg

Telgenkamp

et al. 2022

J Endocrinol Invest

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“…(23) The correlation between hypertriglyceridemia/HS and hypoglycemia in the current study further supports our previous work showing that hypoglycemia in hepatocyte-specific, G6PC-deficient mice arrests VLDL-TG catabolism and enhances hepatic FFA influx, resulting in more pronounced hypertriglyceridemia and HS. (34) Taken together, we propose that the relationship between hepatic G6PC activity and hypertriglyceridemia and HS is predominantly determined by the degree of hypoglycemia, rather than solely dependent on enhanced intrahepatic glycolysis and de novo lipogenesis.…”

Section: Discussionmentioning

confidence: 66%

Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐associated protein 9–Mediated Gene Editing

et al. 2021

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BaCKgRoUND aND aIMS: Patients with glycogen storage disease type 1a (GSD-1a) primarily present with lifethreatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, such as liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD-1a patients. Currently available GSD-1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene-gene interactions (GGIs) in the liver.appRoaCH aND ReSUltS: To meet these needs, we generated and characterized a hepatocyte-specific GSD-1a mouse model using somatic CRISPR/CRISPR-associated protein 9 (Cas9)-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element-binding protein, a transcription factor that is activated in GSD-1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD-1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS. CoNClUSIoNS:In conclusion, we show that somatic CRISPR/Cas9-mediated gene editing allows for the modeling of a spectrum of hepatocyte-borne GSD-1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD-1a and other genetic liver diseases.

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“…The G6P transporter is responsible for moving G6P from the cytoplasm into the ER lumen; therefore, the G6P transporter/G6Pase complex is responsible for glucose production by catalysing the terminal step of both the glycogenolysis and gluconeogenesis pathways [16]. G6P accumulation, secondary to G6Pase deficiency, may contribute to some of the observed metabolic perturbations in patients with GSDIa, such as hyperlactataemia, hyperuricaemia, hyperlipidaemia (studied and reviewed in [17]) and imbalanced cortisol homeostasis [18,19].…”

Section: Pathophysiology and Clinical Manifestationsmentioning

confidence: 99%

Glycogen Storage Disease Type Ia: Current Management Options, Burden and Unmet Needs

et al. 2021

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Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.

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Impaired Very‐Low‐Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia

Cited by 13 publications

References 70 publications

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a

Serum sex hormone-binding globulin levels are reduced and inversely associated with intrahepatic lipid content and saturated fatty acid fraction in adult patients with glycogen storage disease type 1a

Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR‐associated protein 9–Mediated Gene Editing

Glycogen Storage Disease Type Ia: Current Management Options, Burden and Unmet Needs

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