Enhanced Liver Regeneration after Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability

Jun Peng, Jingwei Yu, Hu Xu, Chen Kang, Philip W. Shaul, Youfei Guan, Xiaoyan Zhang, Wen Su

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.

Original languageEnglish (US)
Pages (from-to)784-799
Number of pages16
JournalCellular Physiology and Biochemistry
Volume47
Issue number2
DOIs
StatePublished - Jun 1 2018

Fingerprint

Sterol Regulatory Element Binding Protein 1
Liver Regeneration
Hepatectomy
Cholesterol
Liver
Protein Deficiency
Hepatocytes
Lipids
Triglycerides
Fatty Acids
Staining and Labeling
Lipid Metabolism
Sterol Regulatory Element Binding Protein 2
Gene Expression
Bromodeoxyuridine
Real-Time Polymerase Chain Reaction
Cell Cycle
Oxidoreductases
Homeostasis
Down-Regulation

Keywords

  • Cholesterol
  • Liver regeneration
  • Srebp-1c-/- mice
  • Triglyceride

ASJC Scopus subject areas

  • Physiology

Cite this

Enhanced Liver Regeneration after Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability. / Peng, Jun; Yu, Jingwei; Xu, Hu; Kang, Chen; Shaul, Philip W.; Guan, Youfei; Zhang, Xiaoyan; Su, Wen.

In: Cellular Physiology and Biochemistry, Vol. 47, No. 2, 01.06.2018, p. 784-799.

Research output: Contribution to journalArticle

@article{77c73d007e874a42888bf1ce7bd6061d,
title = "Enhanced Liver Regeneration after Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability",
abstract = "Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.",
keywords = "Cholesterol, Liver regeneration, Srebp-1c-/- mice, Triglyceride",
author = "Jun Peng and Jingwei Yu and Hu Xu and Chen Kang and Shaul, {Philip W.} and Youfei Guan and Xiaoyan Zhang and Wen Su",
year = "2018",
month = "6",
day = "1",
doi = "10.1159/000490030",
language = "English (US)",
volume = "47",
pages = "784--799",
journal = "Cellular Physiology and Biochemistry",
issn = "1015-8987",
publisher = "S. Karger AG",
number = "2",

}

TY - JOUR

T1 - Enhanced Liver Regeneration after Partial Hepatectomy in Sterol Regulatory Element-Binding Protein (SREBP)-1c-Null Mice is Associated with Increased Hepatocellular Cholesterol Availability

AU - Peng, Jun

AU - Yu, Jingwei

AU - Xu, Hu

AU - Kang, Chen

AU - Shaul, Philip W.

AU - Guan, Youfei

AU - Zhang, Xiaoyan

AU - Su, Wen

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.

AB - Background/Aims: Transient lipid accumulation within hepatocytes preceding the peak proliferative process is a characteristic feature of liver regeneration. However, molecular mediators responsible for this lipid accumulation and their functions are not well defined. Sterol regulatory element-binding proteins-1c (SREBP-1c) are critical transcriptional factors that regulate lipid homeostasis in the liver. We hypothesized that SREBP-1c deficiency induced alterations of lipid metabolism may influence hepatocyte proliferation and liver regeneration. Methods: 2/3 partial hepatectomy (PH) was performed in wild type C57BL/6J (WT) and Srebp-1c-/- mice. The lipid contents in serum and liver were measured by enzymatic colorimetric methods. Hepatic lipid droplets were detected by Oil Red O staining and immunohistological staining. Hepatic expression of genes involved in lipid metabolism and cellular proliferation was determined by real-time PCR and/or immunoblot. Hepatocyte proliferation and liver regeneration were assessed by BrdU staining and the weight of remanent liver lobes in Srebp-1c-/- mice, respectively. Results: Srebp-1c-/- mice displayed reduced triglyceride and fatty acids but increased cholesterol in the liver before PH. In response to PH, hepatocellular DNA synthesis was elevated and cell cycle progression was prolonged in Srebp-1c-/- mice, which was associated with enhanced liver regeneration. However, Srebp-1c-/- mice had comparable triglyceride and fatty acid contents and expressions of related genes compared with WT mice during the liver regeneration. In contrast, SREBP-1c-deficiency-induced alteration of cholesterol metabolism was retained during the liver regeneration after PH. Srebp-1c-/- mice exhibited higher cholesterol contents and enhanced expression of SREBP-2 and 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR) in the liver than WT mice after PH. Moreover, downregulation of genes involved in cholesterol elimination was observed after PH in Srebp-1c-/- mice. Conclusion: SREBP-1c deficiency in mice did not interfere with triglyceride and fatty acid metabolism but was associated with significant changes in cholesterol profiles during liver regeneration after PH. These results suggest that increased hepatocellular cholesterol storage and cholesterol availability with the enhanced liver regeneration are identified in Srebp-1c-/- mice. This study also shows that providing requisite cholesterol levels to proliferating hepatocytes and keeping appropriate cholesterol metabolism are required for normal liver regeneration.

KW - Cholesterol

KW - Liver regeneration

KW - Srebp-1c-/- mice

KW - Triglyceride

UR - http://www.scopus.com/inward/record.url?scp=85048950479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048950479&partnerID=8YFLogxK

U2 - 10.1159/000490030

DO - 10.1159/000490030

M3 - Article

VL - 47

SP - 784

EP - 799

JO - Cellular Physiology and Biochemistry

JF - Cellular Physiology and Biochemistry

SN - 1015-8987

IS - 2

ER -