Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal Mice

Du, Hong; Zhao, Ting; Ding, Xinchun

doi:10.1016/j.ajpath.2015.05.021

Cited by 40 publications

(34 citation statements)

References 38 publications

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“…The role of lipophagy in cancer has not been addressed by many studies so far. While several reports have indicated tumour promoting effects of lipophagy [ 261 , 262 ], most studies so far suggest that lipophagy restricts tumourigenesis [ 263 , 264 , 265 , 266 ]. Microtubule-associated protein 1S (MAP1S)-mediated lipophagy promotes lipid droplet clearance and higher levels of MAP1S have been associated with reduced tumour growth and metastasis and an increased patient survival in clear-cell renal cell carcinoma [ 263 ].…”

Section: Lipid Droplets and Autophagy/lipophagymentioning

confidence: 99%

“…Recent evidence suggests that LAL plays a tumour suppressor role and its deficiency in mice has been linked with spontaneous tumourigenesis. Importantly, LAL re-expression in hepatocytes prevents liver metastases [ 265 ] and its reintroduction in the lung reduces inflammation and metastasis in lung cancer [ 266 ]. Interestingly, it was found recently that adipocyte-derived FAs upregulate FA oxidation and stimulate AMPK-dependent autophagy in neighbouring cancer cells [ 267 ].…”

Section: Lipid Droplets and Autophagy/lipophagymentioning

confidence: 99%

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Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

2018

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Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress. Their biogenesis is induced by nutrient and oxidative stress and they accumulate in various cancers. Lipid droplets act as switches that coordinate lipid trafficking and consumption for different purposes in the cell, such as energy production, protection against oxidative stress or membrane biogenesis during rapid cell growth. They sequester toxic lipids, such as fatty acids, cholesterol and ceramides, thereby preventing lipotoxic cell damage and engage in a complex relationship with autophagy. Here, we focus on the emerging mechanisms of stress-induced lipid droplet biogenesis; their roles during nutrient, lipotoxic, and oxidative stress; and the relationship between lipid droplets and autophagy. The recently discovered principles of lipid droplet biology can improve our understanding of the mechanisms that govern cancer cell adaptability and resilience to stress.

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Section: Lipid Droplets and Autophagy/lipophagymentioning

confidence: 99%

Section: Lipid Droplets and Autophagy/lipophagymentioning

confidence: 99%

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

2018

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“…In controlling neutral lipid metabolism, liver homeostasis, immune response and tumor metastasis, lipase [also termed LAL, encoded by lipase A, lysosomal acid type (LIPA)] is a critical metabolic enzyme, which was identified in the current study to be upregulated. Tumor-promoting myeloid-derived suppressive cells in the liver of LAL −/− mice were reported to be reduced by human LIPA expression (21). TNFRSF12A expression in HCC tissue was detected to be 5.3 and 6.9 times higher than in adjacent tissue through RT-qPCR and microarray, respectively.…”

Section: Resultsmentioning

confidence: 99%

Knockdown of the differentially expressed gene TNFRSF12A inhibits hepatocellular carcinoma cell proliferation and migration in vitro

Wang

et al. 2017

Molecular Medicine Reports

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Human hepatocellular carcinoma (HCC) has been reported to be highly insensitive to conventional chemotherapy. In the current study, the Agilent Whole Human Genome Oligo Microarray (4×44 K) was used in order to identify the differentially expressed genes between HCC and adjacent tissues, and the top 22 differentially expressed genes were confirmed through reverse transcription-quantitative polymerase chain reaction. Among the identified differences in gene expression, expression of tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) was markedly higher in HCC tissue than in adjacent tissue. Previous studies have suggested that TNFRSF12A may serve a role in tumor growth and metastasis, thus in the current study, TNFRSF12A was knocked down in the SMMC7721 cell line through siRNA. This demonstrated that cells exhibited reduced reproductive and metastatic capacity ex vivo. Thus, the results of the current study suggest that TNFRSF12A may be a candidate therapeutic target for cancer including HCC, and additional genes that exhibited significantly different expression from normal adjacent tissues require further study.

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“…Indeed, liver-specific LIPA deficiency is associated with dyslipidemia and increased cholesteryl ester storage [19]. Restoration of LAL activity through virusmediated transduction or transgenics in mouse models of LALD and liver-transplantation in LALD patients has proven beneficial [11,[20][21][22][23][24]. Of course, both gene replacement and liver transplantation create a sustained reservoir of LAL-producing cells, capable of widely distributing enzyme for uptake into all tissues via the mannose-6-phosphate receptor.…”

Section: Discussionmentioning

confidence: 99%

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

Pritchard

Strong

Fıçıcıoğlu

2020

Orphanet J Rare Dis

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Background: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. Methods: A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy. Results: Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme. Conclusion: Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.

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Hepatocyte-Specific Expression of Human Lysosome Acid Lipase Corrects Liver Inflammation and Tumor Metastasis in lal Mice

Cited by 40 publications

References 38 publications

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

Lipid Droplets in Cancer: Guardians of Fat in a Stressful World

Knockdown of the differentially expressed gene TNFRSF12A inhibits hepatocellular carcinoma cell proliferation and migration in vitro

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

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