Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=29853564
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Metformin and AMP Kinase Activation Increase Expression of the Sterol
Transporters ABCG5/8 (ATP-Binding Cassette Transporter G5/G8) With Potential
Antiatherogenic Consequences
#MMPMID29853564
Molusky MM
; Hsieh J
; Lee SX
; Ramakrishnan R
; Tascau L
; Haeusler RA
; Accili D
; Tall AR
Arterioscler Thromb Vasc Biol
2018[Jul]; 38
(7
): 1493-1503
PMID29853564
show ga
OBJECTIVE: The mechanisms underlying the cardiovascular benefit of the
anti-diabetic drug metformin are poorly understood. Recent studies have suggested
metformin may upregulate macrophage reverse cholesterol transport. The final
steps of reverse cholesterol transport are mediated by the sterol transporters,
ABCG5 (ATP-binding cassette transporter G5) and ABCG8 (ATP-binding cassette
transporter G8), which facilitate hepato-biliary transport of cholesterol. This
study was undertaken to assess the possibility that metformin induces Abcg5 and
Abcg8 expression in liver and to elucidate the underlying mechanisms. APPROACH
AND RESULTS: Metformin-treated mouse or human primary hepatocytes showed
increased expression of Abcg5/8 and the bile salt export pump, Bsep.
Administration of metformin to Western-type diet-fed mice showed significant
upregulation of Abcg5/8 and Bsep. This resulted in increased initial clearance of
(3)H-cholesteryl ester HDL (high-density lipoprotein) from plasma. However, fecal
(3)H-cholesterol output was only marginally increased, possibly reflecting
increased hepatic Ldlr (low-density lipoprotein receptor) expression, which would
increase nonradiolabeled cholesterol uptake. Abcg5/8 undergo strong circadian
variation. Available chromatin immunoprecipitation-Seq data suggested multiple
binding sites for Period 2, a transcriptional repressor, within the Abcg5/8
locus. Addition of AMPK (5' adenosine monophosphate-activated protein kinase)
agonists decreased Period 2 occupancy, suggesting derepression of Abcg5/8.
Inhibition of ATP citrate lyase, which generates acetyl-CoA from citrate, also
decreased Period 2 occupancy, with concomitant upregulation of Abcg5/8. This
suggests a mechanistic link between feeding-induced acetyl-CoA production and
decreased cholesterol excretion via Period 2, resulting in inhibition of Abcg5/8
expression. CONCLUSIONS: Our findings provide partial support for the concept
that metformin may provide cardiovascular benefit via increased reverse
cholesterol transport but also indicate increased Ldlr expression as a potential
additional mechanism. AMPK activation or ATP citrate lyase inhibition may mediate
antiatherogenic effects through increased ABCG5/8 expression.
|AMP-Activated Protein Kinases/deficiency/genetics/*metabolism
[MESH]
|ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
[MESH]
|ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics/*metabolism
[MESH]
|ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics/*metabolism
[MESH]
free
free
free
