The role of glucosylceramide and glucosylceramide synthase in liver disease: from bench to bedside

Gan, Jian; Zheng, Shuai; Mao, Xiao Rong; Li, Jun Feng

doi:10.18388/abp.2020_5478

Cited by 3 publications

(2 citation statements)

References 47 publications

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“…The liver is not only a major metabolic organ but also an important immune system organ. Moreover, its various constituent cells (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, and natural killer T (NKT) cells) are involved in several immune responses (Gan et al, 2020;Zhang et al, 2019). Physical and chemical factors, viruses, drugs, and alcohol can lead to chronic hepatocyte injury, apoptosis, and necrosis via the activation of immune responses, thus resulting in liver diseases such as viral hepatitis, drug-induced liver injury, autoimmune liver disease, and alcoholic liver disease (Smyk et al, 2018;Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury

Gan

Gao

Wang

et al. 2021

PeerJ

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Background Sphingolipids produce pleiotropic signaling pathways, and participate in the pathological mechanism of hepatocyte apoptosis and necrosis during liver injury. However, the role of glucosylceramide synthase (GCS)–key enzyme that catalyzes the first glycosylation step, in liver injury is still vague. Methods All experiments were conducted using 7–9-week-old pathogen-free male C57BL/6 mice. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected in murine models of liver disease, in addition to histological characterization of liver injuries. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the relative expression of the GCS, matrix metallopeptidase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) genes. The GCS was observed through a fluorescence microscope, and the flow cytometry was used to detect hepatocyte apoptosis. The concentrations of serum IL-4, IL-6, and IL-10 were measured using enzyme-linked immune-sorbent assay (ELISA) kit. MMP-1 and TIMP-1 protein expression was measured via western blot (WB) analysis. Results Con A is often used as a mitogen to activate T lymphocytes and promote mitosis. A single dose of Con A injected intravenously will cause a rapid increase of ALT and AST, which is accompanied by the release of cytokines that cause injury and necrosis of hepatocytes. In this study, we successfully induced acute immune hepatitis in mice by Con A. Con A administration resulted in GCS upregulation in liver tissues. Moreover, the mice in the Con A group had significantly higher levels of ALT, AST, IL-4, IL-6, IL-10 and increased hepatocyte apoptosis than the control group. In contrast, all of the aforementioned genes were significantly downregulated after the administration of a GCS siRNA or Genz-123346 (i.e., a glucosylceramide synthase inhibitor) to inhibit the GCS gene. Additionally, the histopathological changes observed herein were consistent with our ALT, AST, IL-4, IL-6, and IL-10 expression results. However, unlike this, hepatocyte apoptosis has been further increased on the basis of the Con A group. Moreover, our qRT-PCR and WB results indicated that the expression of MMP-1 in the Con A group was significantly lower than that in the control group, whereas TIMP-1 exhibited the opposite trend. Conversely, MMP-1 expression in the GCS siRNA and Genz-123346 groups was higher than that in the Con A group, whereas TIMP-1 expression was lower. Conclusions GCS inhibition reduces Con A-induced immune-mediated liver injury in mice, which may be due to the involvement of GCS in the hepatocyte repair process after injury.

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Section: Discussionmentioning

confidence: 99%

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury

Gan

Gao

Wang

et al. 2021

PeerJ

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“…Gaucher disease is a rare, autosomal recessive genetic disorder, which affects 1/40,000 to 1/60,000 live births [ 43 , 54 , 55 ]. Gaucher disease occurs due to the mutations in GBA1 (in human)/ Gba1 (in mouse) which leads to the functional disruption of the enzyme, Acid β-glucosidase (GCase; EC 4.2.1.25) responsible for the biochemical degradation of GC and GS that are essential for the proper function of skin, cell survival, and embryonal development [ 56 , 57 , 58 , 59 ]. The genetic deficiency of GCase and consequent excess Mϕs and microglial cell accumulation of GC and GS affect both visceral organs and the brain in Gaucher disease [ 36 , 60 ].…”

Section: Gaucher-disease-associated Neuroinflammation: Deciphering Th...mentioning

confidence: 99%

Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases

Pandey

2023

Biomedicines

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Lysosomal storage diseases are a group of rare and ultra-rare genetic disorders caused by defects in specific genes that result in the accumulation of toxic substances in the lysosome. This excess accumulation of such cellular materials stimulates the activation of immune and neurological cells, leading to neuroinflammation and neurodegeneration in the central and peripheral nervous systems. Examples of lysosomal storage diseases include Gaucher, Fabry, Tay–Sachs, Sandhoff, and Wolman diseases. These diseases are characterized by the accumulation of various substrates, such as glucosylceramide, globotriaosylceramide, ganglioside GM2, sphingomyelin, ceramide, and triglycerides, in the affected cells. The resulting pro-inflammatory environment leads to the generation of pro-inflammatory cytokines, chemokines, growth factors, and several components of complement cascades, which contribute to the progressive neurodegeneration seen in these diseases. In this study, we provide an overview of the genetic defects associated with lysosomal storage diseases and their impact on the induction of neuro-immune inflammation. By understanding the underlying mechanisms behind these diseases, we aim to provide new insights into potential biomarkers and therapeutic targets for monitoring and managing the severity of these diseases. In conclusion, lysosomal storage diseases present a complex challenge for patients and clinicians, but this study offers a comprehensive overview of the impact of these diseases on the central and peripheral nervous systems and provides a foundation for further research into potential treatments.

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Integrated microbiome-metabolome reveals thiram aggravates tibial dyschondroplasia through disturbing sphingolipid metabolism

Liu

et al. 2023

Preprint

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As a pesticide, thiram is widely used in agriculture to eliminate pests, and it also causes great environmental pollution and poses a certain threat to animal health. It’s well known that the contamination of feed with thiram in the environment can lead to tibial chondrogenesis(TD) in chickens. The imbalance of intestinal flora and related metabolites is closely related to bone development. Unfortunately, the relationship between the intestinal flora of TD broilers and serum metabolites is unclear. Our results demonstrated that broilers exposed to thiram showed typical lameness and the white cartilage thrombus in the growth plate, accompanied by hepatotoxicity and intestinal injury. We found that the intestinal flora of TD group was out of balance, the diversity was significantly increased with Corynebacterium significantly enriched. Moreover, the metabolome results showed alterations in 10 serum metabolites, with Glucosylceramide being considerably up-regulated, resulting in sphingolipid metabolism problem, which is critical in the etiology of TD. The comprehensive correlation analysis showed the relationship between intestinal microflora and Sphingolipid metabolism in TD broilers. Thiram aggravates tibial chondrodysplasia by affecting the changes in the composition and structure of the intestinal microflora of broilers and the disorder of sphingomyelin metabolism. Collectively, these findings provide novel insight into the pathogenesis of TD from the perspective of thiram-induced gut microbiota and metabolic disorders.

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The role of glucosylceramide and glucosylceramide synthase in liver disease: from bench to bedside

Cited by 3 publications

References 47 publications

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury

Glucosylceramide synthase regulates hepatocyte repair after concanavalin A-induced immune-mediated liver injury

Exploring Pro-Inflammatory Immunological Mediators: Unraveling the Mechanisms of Neuroinflammation in Lysosomal Storage Diseases

Integrated microbiome-metabolome reveals thiram aggravates tibial dyschondroplasia through disturbing sphingolipid metabolism

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