Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression

Allyson N. Hamlin, Sivaprakasam Chinnarasu, Yinyuan Ding, Xunde Xian, Joachim Herz, Anja Jaeschke, David Y. Hui

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Reduced low-density lipoprotein receptor–related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet–induced hepatic insulin resistance and hepatic steatosis in vivo. The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1/ mice with normal LRP1 expression and hLrp1/ mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1/ mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1/ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1/ mice. The accelerated liver pathology observed in HFHC-fed hLrp1/ mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1/ hepatocytes than in hLrp1/ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.

Original languageEnglish (US)
Pages (from-to)9674-9684
Number of pages11
JournalJournal of Biological Chemistry
Volume293
Issue number25
DOIs
StatePublished - Jan 1 2018

Fingerprint

Dietary Cholesterol
Fatty Liver
LDL Lipoproteins
Liver
Lipoproteins
Hepatocytes
Protein Deficiency
Cholesterol
Proteins
Fats
Inflammation
Liver Cirrhosis
Disease Progression
Liver Diseases
Genes
Deficiency Diseases
Gene Expression
Hepatic Stellate Cells
Palmitates
High Fat Diet

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression. / Hamlin, Allyson N.; Chinnarasu, Sivaprakasam; Ding, Yinyuan; Xian, Xunde; Herz, Joachim; Jaeschke, Anja; Hui, David Y.

In: Journal of Biological Chemistry, Vol. 293, No. 25, 01.01.2018, p. 9674-9684.

Research output: Contribution to journalArticle

Hamlin, Allyson N. ; Chinnarasu, Sivaprakasam ; Ding, Yinyuan ; Xian, Xunde ; Herz, Joachim ; Jaeschke, Anja ; Hui, David Y. / Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 25. pp. 9674-9684.
@article{e1af0d92e2b242e68246a446d2d4b182,
title = "Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression",
abstract = "Reduced low-density lipoprotein receptor–related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet–induced hepatic insulin resistance and hepatic steatosis in vivo. The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1/ mice with normal LRP1 expression and hLrp1/ mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1/ mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1/ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1/ mice. The accelerated liver pathology observed in HFHC-fed hLrp1/ mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1/ hepatocytes than in hLrp1/ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.",
author = "Hamlin, {Allyson N.} and Sivaprakasam Chinnarasu and Yinyuan Ding and Xunde Xian and Joachim Herz and Anja Jaeschke and Hui, {David Y.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1074/jbc.RA118.001952",
language = "English (US)",
volume = "293",
pages = "9674--9684",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "25",

}

TY - JOUR

T1 - Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression

AU - Hamlin, Allyson N.

AU - Chinnarasu, Sivaprakasam

AU - Ding, Yinyuan

AU - Xian, Xunde

AU - Herz, Joachim

AU - Jaeschke, Anja

AU - Hui, David Y.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Reduced low-density lipoprotein receptor–related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet–induced hepatic insulin resistance and hepatic steatosis in vivo. The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1/ mice with normal LRP1 expression and hLrp1/ mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1/ mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1/ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1/ mice. The accelerated liver pathology observed in HFHC-fed hLrp1/ mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1/ hepatocytes than in hLrp1/ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.

AB - Reduced low-density lipoprotein receptor–related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet–induced hepatic insulin resistance and hepatic steatosis in vivo. The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1/ mice with normal LRP1 expression and hLrp1/ mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1/ mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1/ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1/ mice. The accelerated liver pathology observed in HFHC-fed hLrp1/ mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1/ hepatocytes than in hLrp1/ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.

UR - http://www.scopus.com/inward/record.url?scp=85048948987&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048948987&partnerID=8YFLogxK

U2 - 10.1074/jbc.RA118.001952

DO - 10.1074/jbc.RA118.001952

M3 - Article

C2 - 29752404

AN - SCOPUS:85048948987

VL - 293

SP - 9674

EP - 9684

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 25

ER -