Introduction:
MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote degradation. Recent reports, including ours, indicated that miR-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Unexpectedly, miR-33 deficient (miR-33
-/-
) mice fed high fat diet (HFD) developed severe fatty liver and the mechanisms were investigated.
Methods and Results:
The liver weight of miR-33
-/-
mice were about 1.5 times heavier than that of miR-33
+/+
mice and histological examination revealed that miR-33
-/-
mice developed severe fatty liver under HFD feeding. In order to determine the cause of the fatty liver observed in miR-33
-/-
mice fed HFD, we analysed the gene expression profiles using the liver of miR-33
+/+
and miR-33
-/-
mice fed normal chow at the age of 16 weeks when they didn’t show fatty liver. As a result, genes involved in fatty acid metabolism were upregulated in miR-33
-/-
mice. Among them we found SREBP-1 as a new potential target gene of miR-33
in silico
and confirmed that miR-33 targets the 3’UTR of SREBP-1
in
vitro
. The expression of SREBP-1 and
de novo
fatty acid production were significantly increased in the liver of miR-33
-/-
mice. We further intercrossed miR-33
-/-
mice with
Srebf1
+/-
mice and fed them HFD. Hepatic steatosis was reversed in miR-33
-/-
Srebf1
+/-
mice compared with miR-33
-/-
Srebf1
+/+
mice by histological analysis and measurement of triglyceride levels. The expression levels of genes involved in fatty acid synthesis, including
Scd1, Fasn, Acc1
, and
Pparg
were increased in miR-33
-/-
Srebf1
+/+
mice compared with miR-33
+/+
Srebf1
+/+
mice, and those increase were reversed in miR-33
-/-
Srebf1
+/-
mice.
Conclusions:
miR-33 regulates lipogenic pathway via regulating SREBP-1 as a novel target
in vivo
. In sterol-depleted conditions, acetyl-CoA might be preferred as a substrate for cholesterol production and not for fatty acid production by the downregulation of SREBP-1 through the upregulation of miR-33. Conversely, in cholesterol-rich condition, acetyl-CoA might be preferred as a substrate for fatty acid production through the downregulation of miR-33.
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