LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway

Chen, Ziye; Chen, Lu; Sun, Bo; Liu, Dongming; He, Yuchao; Qi, Lisha; Li, Guangtao; Han, Zhiqiang; Zhan, Linlin; Zhang, Su; Zhu, Keyun; Luo, Yi; Chen, Liwei; Zhang, Ning; Guo, Hua

doi:10.1016/j.molmet.2021.101230

Cited by 49 publications

(31 citation statements)

References 53 publications

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“…Interestingly, a decreased ability to utilise circulating cholesterol was associated with increased HCC proliferation and metastasis. 250 Furthermore, cholesterol synthesis was shown to support HCC growth in the absence of FASN, 216 which indicates crosstalk between DNL and cholesterol synthesis. Similarly, increased cholesterol and BA synthesis, through PPARα activation, cause cholestasis, liver damage, and finally CCA development.…”

Section: Deregulation Of Lipid Metabolism In Liver Cancermentioning

confidence: 99%

Lipid alterations in chronic liver disease and liver cancer

2022

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Section: Deregulation Of Lipid Metabolism In Liver Cancermentioning

confidence: 99%

Lipid alterations in chronic liver disease and liver cancer

2022

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“…Interestingly, the downregulation of LDLR that mediates the endocytosis of LDL cholesterol, increases the risk of human HCC. The mechanistic study demonstrated that the reduced LDLR expression promoted intracellular de novo cholesterol biosynthesis to compensate the decreased LDL uptake ( Chen et al, 2021 ). Altogether, these preclinical studies provide compelling evidence that cholesterol is an independent risk factor for NASH and fibrosis, and substantially increase the risk of HCC ( Figure 2 ).…”

Section: Cholesterol and The Pathogenesis Of Hccmentioning

confidence: 99%

Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

Zhou

Sun

2021

Front. Cell Dev. Biol.

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Hepatocellular carcinoma (HCC) represents a leading cause of cancer-related deaths globally. The rising incidence of metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as the fastest-growing cause of HCC in recent years. Cholesterol, a major lipid component of the cell membrane and lipoprotein particles, is primarily produced and metabolized by the liver. Numerous studies have revealed an increased cholesterol biosynthesis and uptake, reduced cholesterol exportation and excretion in HCC, which all contribute to lipotoxicity, inflammation, and fibrosis, known HCC risk factors. In contrast, some clinical studies have shown that higher cholesterol is associated with a reduced risk of HCC. These contradictory observations imply that the relationship between cholesterol and HCC is far more complex than initially anticipated. Understanding the role of cholesterol and deciphering the underlying molecular events in HCC development is highly relevant to developing new therapies. Here, we discuss the current understanding of cholesterol metabolism in the pathogenesis of NAFLD-associated HCC, and the underlying mechanisms, including the roles of cholesterol in the disruption of normal function of specific cell types and signaling transduction. We also review the clinical progression in evaluating the association of cholesterol with HCC. The therapeutic effects of lowering cholesterol will also be summarized. We also interpret reasons for the contradictory observations from different preclinical and human studies of the roles of cholesterol in HCC, aiming to provide a critical assessment of the potential of cholesterol as a therapeutic target.

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“…Likewise, LDL clearance was greatly increased during prostate and lung cancer progression [44,45], suggesting LDL-cholesterol supports metastatic behavior. Despite these findings, and possibly due to an increased reliance on upregulated cholesterol biosynthesis, others have correlated low LDLR levels with poor prognosis and clinical outcomes in HCC, prostate and cervical cancer [46][47][48].…”

Section: Increased Ldl-cholesterol Uptake Supports Cancer Growth and ...mentioning

confidence: 99%

Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

Nguyen

Jose

Wahba

et al. 2022

IJMS

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Cancer cells undergo drastic metabolic adaptions to cover increased bioenergetic needs, contributing to resistance to therapies. This includes a higher demand for cholesterol, which often coincides with elevated cholesterol uptake from low-density lipoproteins (LDL) and overexpression of the LDL receptor in many cancers. This implies the need for cancer cells to accommodate an increased delivery of LDL along the endocytic pathway to late endosomes/lysosomes (LE/Lys), providing a rapid and effective distribution of LDL-derived cholesterol from LE/Lys to other organelles for cholesterol to foster cancer growth and spread. LDL-cholesterol exported from LE/Lys is facilitated by Niemann–Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families. In addition, lysosomal membrane proteins, small Rab GTPases as well as scaffolding proteins, including annexin A6 (AnxA6), contribute to regulating cholesterol egress from LE/Lys. Here, we summarize current knowledge that links upregulated activity and expression of cholesterol transporters and related proteins in LE/Lys with cancer growth, progression and treatment outcomes. Several mechanisms on how cellular distribution of LDL-derived cholesterol from LE/Lys influences cancer cell behavior are reviewed, some of those providing opportunities for treatment strategies to reduce cancer progression and anticancer drug resistance.

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LDLR inhibition promotes hepatocellular carcinoma proliferation and metastasis by elevating intracellular cholesterol synthesis through the MEK/ERK signaling pathway

Cited by 49 publications

References 53 publications

Lipid alterations in chronic liver disease and liver cancer

Lipid alterations in chronic liver disease and liver cancer

Cholesterol Metabolism: A Double-Edged Sword in Hepatocellular Carcinoma

Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance

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