Deranged hepatocyte intracellular Ca2+ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma

Eunus S. Ali, Grigori Rychkov, Greg J. Barritt

Research output: Contribution to journalReview article

1 Citation (Scopus)

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC. Changes in intracellular Ca2+ constitute important signaling pathways for the regulation of lipid and carbohydrate metabolism in normal hepatocytes. Recent studies of steatotic hepatocytes have identified lipid-induced changes in intracellular Ca2+, and have provided evidence that altered Ca2+ signaling exacerbates lipid accumulation and may promote HCC. The aims of this review are to summarise current knowledge of the lipid-induced changes in hepatocyte Ca2+ homeostasis, to comment on the mechanisms involved, and discuss the pathways leading from altered Ca2+ homeostasis to enhanced lipid accumulation and the potential promotion of HCC. In steatotic hepatocytes, lipid inhibits store-operated Ca2+ entry and SERCA2b, and activates Ca2+ efflux from the endoplasmic reticulum (ER) and its transfer to mitochondria. These changes are associated with changes in Ca2+ concentrations in the ER (decreased), cytoplasmic space (increased) and mitochondria (likely increased). They lead to: inhibition of lipolysis, lipid autophagy, lipid oxidation, and lipid secretion; activation of lipogenesis; increased lipid; ER stress, generation of reactive oxygen species (ROS), activation of Ca2+/calmodulin-dependent kinases and activation of transcription factor Nrf2. These all can potentially mediate the transition of NAFLD to HCC. It is concluded that lipid-induced changes in hepatocyte Ca2+ homeostasis are important in the initiation and progression of HCC. Further research is desirable to better understand the cause and effect relationships, the time courses and mechanisms involved, and the potential of Ca2+ transporters, channels, and binding proteins as targets for pharmacological intervention.

LanguageEnglish
Article number102057
JournalCell Calcium
Volume82
DOIs
Publication statusPublished - 1 Sep 2019

Keywords

  • Ca
  • Endoplasmic reticulum
  • Hepatocellular carcinoma
  • Hepatocytes
  • Non alcoholic fatty liver disease
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Deranged hepatocyte intracellular Ca2+ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma",
abstract = "Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC. Changes in intracellular Ca2+ constitute important signaling pathways for the regulation of lipid and carbohydrate metabolism in normal hepatocytes. Recent studies of steatotic hepatocytes have identified lipid-induced changes in intracellular Ca2+, and have provided evidence that altered Ca2+ signaling exacerbates lipid accumulation and may promote HCC. The aims of this review are to summarise current knowledge of the lipid-induced changes in hepatocyte Ca2+ homeostasis, to comment on the mechanisms involved, and discuss the pathways leading from altered Ca2+ homeostasis to enhanced lipid accumulation and the potential promotion of HCC. In steatotic hepatocytes, lipid inhibits store-operated Ca2+ entry and SERCA2b, and activates Ca2+ efflux from the endoplasmic reticulum (ER) and its transfer to mitochondria. These changes are associated with changes in Ca2+ concentrations in the ER (decreased), cytoplasmic space (increased) and mitochondria (likely increased). They lead to: inhibition of lipolysis, lipid autophagy, lipid oxidation, and lipid secretion; activation of lipogenesis; increased lipid; ER stress, generation of reactive oxygen species (ROS), activation of Ca2+/calmodulin-dependent kinases and activation of transcription factor Nrf2. These all can potentially mediate the transition of NAFLD to HCC. It is concluded that lipid-induced changes in hepatocyte Ca2+ homeostasis are important in the initiation and progression of HCC. Further research is desirable to better understand the cause and effect relationships, the time courses and mechanisms involved, and the potential of Ca2+ transporters, channels, and binding proteins as targets for pharmacological intervention.",
keywords = "Ca, Endoplasmic reticulum, Hepatocellular carcinoma, Hepatocytes, Non alcoholic fatty liver disease, Reactive oxygen species",
author = "Ali, {Eunus S.} and Grigori Rychkov and Barritt, {Greg J.}",
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Deranged hepatocyte intracellular Ca2+ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma. / Ali, Eunus S.; Rychkov, Grigori; Barritt, Greg J.

In: Cell Calcium, Vol. 82, 102057, 01.09.2019.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Deranged hepatocyte intracellular Ca2+ homeostasis and the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma

AU - Ali, Eunus S.

AU - Rychkov, Grigori

AU - Barritt, Greg J.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC. Changes in intracellular Ca2+ constitute important signaling pathways for the regulation of lipid and carbohydrate metabolism in normal hepatocytes. Recent studies of steatotic hepatocytes have identified lipid-induced changes in intracellular Ca2+, and have provided evidence that altered Ca2+ signaling exacerbates lipid accumulation and may promote HCC. The aims of this review are to summarise current knowledge of the lipid-induced changes in hepatocyte Ca2+ homeostasis, to comment on the mechanisms involved, and discuss the pathways leading from altered Ca2+ homeostasis to enhanced lipid accumulation and the potential promotion of HCC. In steatotic hepatocytes, lipid inhibits store-operated Ca2+ entry and SERCA2b, and activates Ca2+ efflux from the endoplasmic reticulum (ER) and its transfer to mitochondria. These changes are associated with changes in Ca2+ concentrations in the ER (decreased), cytoplasmic space (increased) and mitochondria (likely increased). They lead to: inhibition of lipolysis, lipid autophagy, lipid oxidation, and lipid secretion; activation of lipogenesis; increased lipid; ER stress, generation of reactive oxygen species (ROS), activation of Ca2+/calmodulin-dependent kinases and activation of transcription factor Nrf2. These all can potentially mediate the transition of NAFLD to HCC. It is concluded that lipid-induced changes in hepatocyte Ca2+ homeostasis are important in the initiation and progression of HCC. Further research is desirable to better understand the cause and effect relationships, the time courses and mechanisms involved, and the potential of Ca2+ transporters, channels, and binding proteins as targets for pharmacological intervention.

AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths in men, and the sixth in women. Non-alcoholic fatty liver disease (NAFLD) is now one of the major risk factors for HCC. NAFLD, which involves the accumulation of excess lipid in cytoplasmic lipid droplets in hepatocytes, can progress to non-alcoholic steatosis, fibrosis, and HCC. Changes in intracellular Ca2+ constitute important signaling pathways for the regulation of lipid and carbohydrate metabolism in normal hepatocytes. Recent studies of steatotic hepatocytes have identified lipid-induced changes in intracellular Ca2+, and have provided evidence that altered Ca2+ signaling exacerbates lipid accumulation and may promote HCC. The aims of this review are to summarise current knowledge of the lipid-induced changes in hepatocyte Ca2+ homeostasis, to comment on the mechanisms involved, and discuss the pathways leading from altered Ca2+ homeostasis to enhanced lipid accumulation and the potential promotion of HCC. In steatotic hepatocytes, lipid inhibits store-operated Ca2+ entry and SERCA2b, and activates Ca2+ efflux from the endoplasmic reticulum (ER) and its transfer to mitochondria. These changes are associated with changes in Ca2+ concentrations in the ER (decreased), cytoplasmic space (increased) and mitochondria (likely increased). They lead to: inhibition of lipolysis, lipid autophagy, lipid oxidation, and lipid secretion; activation of lipogenesis; increased lipid; ER stress, generation of reactive oxygen species (ROS), activation of Ca2+/calmodulin-dependent kinases and activation of transcription factor Nrf2. These all can potentially mediate the transition of NAFLD to HCC. It is concluded that lipid-induced changes in hepatocyte Ca2+ homeostasis are important in the initiation and progression of HCC. Further research is desirable to better understand the cause and effect relationships, the time courses and mechanisms involved, and the potential of Ca2+ transporters, channels, and binding proteins as targets for pharmacological intervention.

KW - Ca

KW - Endoplasmic reticulum

KW - Hepatocellular carcinoma

KW - Hepatocytes

KW - Non alcoholic fatty liver disease

KW - Reactive oxygen species

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U2 - 10.1016/j.ceca.2019.102057

DO - 10.1016/j.ceca.2019.102057

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