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The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. Despite its tremendous significance for public health, we lack a comprehensive understanding of the pathogenic mechanisms of NAFLD and its more advanced stage, nonalcoholic steatohepatitis (NASH). Identification of novel pathways or cellular mechanisms that regulate liver lipid metabolism has profound implications for the understanding of the pathology of NAFLD and NASH. The nuclear envelope is topologically connected to the ER, where protein synthesis and lipid synthesis occurs. Emerging evidence points toward that the nuclear lamins and nuclear membrane-associated proteins are involved in lipid metabolism and homeostasis. We review published reports that link these nuclear envelope proteins to lipid metabolism. In particular, we focus on the recent work demonstrating the essential roles for the nuclear envelope-localized torsinA/lamina-associated polypeptide (LAP1) complex in hepatic steatosis, lipid secretion, and NASH development. We also discuss plausible pathogenic mechanisms by which the loss of either protein in hepatocytes leads to hepatic dyslipidemia and NASH development.

SUBMITTER: Ostlund C

PROVIDER: S-EPMC7602593 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD.

Östlund Cecilia C Hernandez-Ono Antonio A Shin Ji-Yeon JY

Biology 20201015 10

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. Despite its tremendous significance for public health, we lack a comprehensive understanding of the pathogenic mechanisms of NAFLD and its more advanced stage, nonalcoholic steatohepatitis (NASH). Identification of novel pathways or cellular mechanisms that regulate liver lipid metabolism has profound implications for the understanding of the pathology of NAFLD and NASH. The nuclear envelope is topologicall ...[more]

PMID: 33076344

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Project description:Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.

Project description:BackgroundSalvia-Nelumbinis naturalis (SNN), the extract of Chinese herbal medicine, has shown effects on NAFLD. This study aims to explore the underlying mechanism of SNN for regulating the lipid metabolism disorder in NAFLD based on the SIRT1/AMPK signaling pathway.MethodsMale C57BL/6J mice fed with a high-fat diet (HFD) were used to establish the NAFLD model. Dynamic changes of mice including body weight, liver weight, serological biochemical indexes, liver histopathological changes, and protein level of AMPK and SIRT1 were monitored. After18 weeks, SNN treatment was administrated to the NAFLD mice for another 4 weeks. Besides the aforementioned indices, TC and TG of liver tissues were also measured. Western blot and quantitative RT-PCR were used to detect the expression and/or activation of SIRT1 and AMPK, as well as the molecules associated with lipid synthesis and β-oxidation. Furthermore, AML12 cells with lipid accumulation induced by fatty acids were treated with LZG and EX527 (SIRT1 inhibitor) or Compound C (AMPK inhibitor ) to confirm the potential pharmacological mechanism.ResultsDynamic observation found the mice induced by HFD with gradually increased body and liver weight, elevated serum cholesterol, hepatic lipid accumulation, and liver injury. After 16 weeks, these indicators have shown obvious changes. Additionally, the hepatic level of SIRT1 and AMPK activation was identified gradually decreased with NAFLD progress. The mice with SNN administration had lower body weight, liver weight, and serum level of LDL-c and ALT than those of the NAFLD model. Hepatosteatosis and hepatic TG content in the liver tissues of the SNN group were significantly reduced. When compared with control mice, the NAFLD mice had significantly decreased hepatic expression of SIRT1, p-AMPK, p-ACC, ACOX1, and increased total Acetylated-lysine, SUV39H2, and SREBP-1c. The administration of SNN reversed the expression of these molecules. In vitro experiments showed the effect of SNN in ameliorating hepatosteatosis and regulating the expression of lipid metabolism-related genes in AML12 cells, which were diminished by EX527 or Compound C co-incubation.ConclusionsTaken together, the SIRT1/AMPK signaling pathway, involved in hepatic lipid synthesis and degradation, plays a pivotal role in the pathogenesis of NAFLD development. The regulation of SIRT1/AMPK signaling greatly contributes to the underlying therapeutic mechanism of SNN for NAFLD.

Dataset Information

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD.

Publications

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD.

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