Hepatic monocyte chemoattractant protein-1 is upregulated by dietary cholesterol and contributes to liver steatosis.
To assess the role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in the development of fatty liver, we have used LDLr(-/-) mice as an animal model of high-fat, high-cholesterol diet-induced liver steatosis. The rapid dietary induction of hepatic mRNA MCP-1 expression was paralleled by a concomitant increase in plasma MCP-1 that was strongly associated with the degree of liver steatosis. Hepatocytes showed an intense immunoreactivity for MCP-1 that was mainly located surrounding the hepatic lipid droplets. The intake of cholesterol also increased the concentration of MCP-1 in liver homogenates. This was accompanied by a differential expression of members of the PPAR family. Additionally, complete MCP-1 deficiency prevents the development of liver steatosis in LDLr(-/-) mice and partial deficiency is accompanied by a certain protective effect. Our data also suggest that MCP-1 may be important in the regulation of hepatic insulin resistance and may represent a link between inflammation and metabolic diseases. We conclude that dietary cholesterol upregulation of hepatic MCP-1 may help to understand the role of circulating MCP-1 in conditions where liver derangements are clinically important and in the association of liver steatosis with the metabolic syndrome.
Rull
Anna
A
Centre de Recerca Biomèdica, Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, c/Sant Joan s/n, 43201 Reus, Spain.
Rodríguez
Fernando
F
Aragonès
Gerard
G
Marsillach
Judit
J
Beltrán
Raúl
R
Alonso-Villaverde
Carlos
C
Camps
Jordi
J
Joven
Jorge
J
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D005234:Fatty Liver / Q000503:physiopathology*; D022781:Hepatocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D018932:Chemokine CCL2; D002791:Cholesterol, Dietary; D012333:RNA, Messenger