Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia

Waskowicz, Lauren R; Zhou, Jin; Landau, Dustin J.; Brooks, Elizabeth D.; Lim, Andrea; Yavarow, Zollie A; Kudo, Tsubasa; Zhang, Haoyue; Wu, Yajun; Grant, Stuart A.; Young, Sarah P.; Huat, Bay Boon; Yen, Paul M.; Koeberl, Dwight D.

doi:10.1093/hmg/ddy343

Cited by 35 publications

(34 citation statements)

References 59 publications

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“…A rational therapeutic approach for the treatment of NAFLD is to increase hepatic energy expenditure and thereby increase hepatic fat oxidation. Recently, we showed that the use of PPAR-α agonists, in particular fenofibrate, prevented NAFLD and hepatic injuries in GSDI, as previously described in diabetes [66][67][68]. Interestingly, the activation of β-oxidation by fenofibrate promoted the utilization of G6P through lipid metabolism, avoiding the accumulation of glycogen [66].…”

Section: Imbalance Of Glucose-6 Phosphate Metabolism Leads To Metabolsupporting

confidence: 53%

Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

2019

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Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.

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Section: Imbalance Of Glucose-6 Phosphate Metabolism Leads To Metabolsupporting

confidence: 53%

Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

2019

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“…For the vast majority of patients, the treatment is limited to treating the symptoms, rather than curing the disease. Still, the administration of small molecules could improve some mitochondrial parameters, and possibly alleviate mitochondrial disease symptoms [28][29][30][31][32]42,43].…”

Section: Discussionmentioning

confidence: 99%

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells

Douiev

Sheffer

Horvath

et al. 2020

Cells

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Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1, or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene result in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, as well as ATP production and oxygen consumption. It improved mitochondrial morphology in the patient’s fibroblasts, although causing a mild increase in ROS production at the same time. A human foreskin fibroblast cell line overexpressing the p.G362S mutation showed aberrant mitochondrial morphology, which normalized in the presence of bezafibrate. Further studies would be needed to show the consistency of the response to bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that bezafibrate could be offered as a treatment option for patients with certain DNM1L mutations.

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“…This is in accord with previously reports by others including us, showing Bezafibrate to be beneficial for certain mitochondrial diseases. This could possibly be attributed to increased ability to utilize fatty acids [29,31,32,34,41] Furthermore, Bezafibrate had a positive effect on mitochondrial morphology, leading to decreased mitochondrial elongated phenotype, which was approaching controls (higher levels of solitary mitochondria, and lower levels of elongated ones). This might indicate that…”

Section: Discussionmentioning

confidence: 95%

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L Deficient Patient Cells

Douiev¹,

Sheffer²,

Horváth³

et al. 2019

Preprint

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Mitochondria are involved in many cellular processes and their main role is cellular energy production. They constantly undergo fission and fusion, and these counteracting processes are under strict balance. The cytosolic dynamin-related protein 1, Drp1 or dynamin-1-like protein (DNM1L) mediates mitochondrial and peroxisomal division. Defects in the DNM1L gene results in a complex neurodevelopmental disorder with heterogeneous symptoms affecting multiple organ systems. Currently there is no curative treatment available for this condition. We have previously described a patient with a de novo heterozygous c.1084G>A (p.G362S) DNM1L mutation and studied the effects of a small molecule, Bezafibrate, on mitochondrial functions in this patient’s fibroblasts compared to controls. Bezafibrate normalized growth on glucose-free medium, ATP production, oxygen consumption and s improved mitochondrial morphology in patient’s fibroblasts, albeit concomitantly causing a mild increase ROS production. Further studies would be needed to show the consistency of the response to Bezafibrate, possibly using fibroblasts from patients with different mutations in DNM1L, and this treatment should be confirmed in clinical trials. However, taking into account the favorable effects in our study, we suggest that Bezafibrate could be a possible treatment option for patients with certain DNM1L mutations.

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Bezafibrate induces autophagy and improves hepatic lipid metabolism in glycogen storage disease type Ia

Cited by 35 publications

References 59 publications

Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L Deficient Patient Cells

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