Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice

Yadati, Tulasi; Houben, Tom; Bitorina, Albert V.; Oligschlaeger, Yvonne; Gijbels, Marion J.J.; Mohren, Ronny; Lütjohann, Dieter; Khurana, Princy; Goyal, Sandeep; Kulkarni, Aditya; Theys, Jan; Cillero‐Pastor, Berta; Shiri-Sverdlov, Ronit

doi:10.3389/fimmu.2021.675535

Cited by 16 publications

(13 citation statements)

References 54 publications

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“…In line with these findings, autophagy-related proteins were also decreased in the liver of obese mice (Yang et al, 2010;Tong et al, 2019). On the other hand, extracellular CTSD function is relevant in the accumulation of hepatic lipids and intracellular CTSD is involved in essential processes, such as mitochondrial oxidative phosphorylation and electron transport function (Yadati et al, 2021). Recently, it was described that administration of the extracellular CTSD inhibitor reduced hepatic triglyceride levels in mice fed with a HFD, whereas intracellular or the extracellular CTSD inhibitor decreased hepatic cholesterol levels (Yadati et al, 2021).…”

Section: Role Of Cathepsins and Autophagy In Obesitysupporting

confidence: 69%

“…On the other hand, extracellular CTSD function is relevant in the accumulation of hepatic lipids and intracellular CTSD is involved in essential processes, such as mitochondrial oxidative phosphorylation and electron transport function (Yadati et al, 2021). Recently, it was described that administration of the extracellular CTSD inhibitor reduced hepatic triglyceride levels in mice fed with a HFD, whereas intracellular or the extracellular CTSD inhibitor decreased hepatic cholesterol levels (Yadati et al, 2021). With these results the authors concluded that extracellular CTSD is involved in pathways related to lipids and inflammation.…”

Section: Role Of Cathepsins and Autophagy In Obesitymentioning

confidence: 99%

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Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells

Cabrera-Reyes

Parra-Ruiz

Yuseff

et al. 2021

Front. Cell Dev. Biol.

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Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

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Section: Role Of Cathepsins and Autophagy In Obesitysupporting

confidence: 69%

Section: Role Of Cathepsins and Autophagy In Obesitymentioning

confidence: 99%

Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells

Cabrera-Reyes

Parra-Ruiz

Yuseff

et al. 2021

Front. Cell Dev. Biol.

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“…S10). Inflammation and oxidative stress are important drivers for NAFLD disease progression [ 27 , 43 , 44 ]. Our data showed that hepatocyte-specific deficiency of HuR significantly increased the expression of macrophage markers, various chemokines, innate immune responses markers, and chemokines in the livers of HuR hKO mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

et al. 2022

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Background NAFLD has become the most common chronic liver disease worldwide. Human antigen R (HuR), an RNA-binding protein, is an important post-transcriptional regulator. HuR has been reported as a key player in regulating lipid homeostasis in the liver and adipose tissues by using tissue-specific HuR knockout mice. However, the underlying mechanism by which hepatocyte-specific HuR regulates hepatic lipid metabolism under metabolic stress remains unclear and is the focus of this study. Methods Hepatocyte-specific HuR deficient mice (HuRhKO) and age-/gender-matched control mice, as well as long-noncoding RNA H19 knockout mice (H19−/−), were fed a Western Diet plus sugar water (WDSW). Hepatic lipid accumulation, inflammation and fibrosis were examined by histology, RNA transcriptome analysis, qRT–PCR, and Western blot analysis. Bile acid composition was measured using LC–MS/MS. Results Hepatocyte-specific deletion of HuR not only significantly increased hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also markedly induced inflammation by increasing immune cell infiltration and neutrophil activation under metabolic stress. In addition, hepatic deficiency of HuR disrupted bile acid homeostasis and enhanced liver fibrosis. Mechanistically, HuR is a repressor of H19 expression. Analysis of a recently published dataset (GSE143358) identified H19 as the top-upregulated gene in liver-specific HuR knockout mice. Similarly, hepatocyte-specific deficiency of HuR dramatically induced the expression of H19 and sphingosine-1 phosphate receptor 2 (S1PR2), but reduced the expression of sphingosine kinase 2 (SphK2). WDSW-induced hepatic lipid accumulation was alleviated in H19−/− mice. Furthermore, the downregulation of H19 alleviated WDSW-induced NAFLD in HuRhKO mice. Conclusions HuR not only functions as an RNA binding protein to modulate post-transcriptional gene expression but also regulates H19 promoter activity. Hepatic HuR is an important regulator of hepatic lipid metabolism via modulating H19 expression.

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“…The enzyme cathepsin D (CTSE) is a lysosomal enzyme and an indicator of NASH [ 60 ]. CTSE inhibitors can be regarded as promising and safe NASH drugs [ 61 ]. The gene DMBT1 harbors homozygous deletions and/or lacks expression in malignant human brain tumors, and it was named deleted in malignant brain tumors 1 (Dmbt1) [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

A Transcriptomic Response to Lactiplantibacillus plantarum-KCC48 against High-Fat Diet-Induced Fatty Liver Diseases in Mice

Ilavenil

Muthusamy

Jung

et al. 2022

IJMS

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The most prevalent chronic liver disorder in the world is fatty liver disease caused by a high-fat diet. We examined the effects of Lactiplantibacillus plantarum-KCC48 on high-fat diet-induced (HFD) fatty liver disease in mice. We used the transcriptome tool to perform a systematic evaluation of hepatic mRNA transcripts changes in high-fat diet (HFD)-fed animals and high-fat diet with L. plantarum (HFLPD)-fed animals. HFD causes fatty liver diseases in animals, as evidenced by an increase in TG content in liver tissues compared to control animals. Based on transcriptome data, 145 differentially expressed genes (DEGs) were identified in the liver of HFD-fed mice compared to control mice. Moreover, 61 genes were differentially expressed in the liver of mice fed the HFLPD compared to mice fed the HFD. Additionally, 43 common DEGs were identified between HFD and HFLPD. These genes were enriched in metabolic processes, retinol metabolism, the PPAR signaling pathway, fatty acid degradation, arachidonic metabolism, and steroid hormone synthesis. Taking these data into consideration, it can be concluded that L. plantarum-KCC48 treatment significantly regulates the expression of genes involved in hepatosteatosis caused by HFD, which may prevent fatty liver disease.

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Inhibition of Extracellular Cathepsin D Reduces Hepatic Lipid Accumulation and Leads to Mild Changes in Inflammationin NASH Mice

Cited by 16 publications

References 54 publications

Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells

Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells

RNA binding protein HuR protects against NAFLD by suppressing long noncoding RNA H19 expression

A Transcriptomic Response to Lactiplantibacillus plantarum-KCC48 against High-Fat Diet-Induced Fatty Liver Diseases in Mice

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