Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis

Abstract

miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33–knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.

Connecting Cholesterol Efflux Factors to Lung Cancer Biology and Therapeutics

“…Interestingly, liver-specific ablation of miR-33 does not lead to increased body weight but rather improves regulation of glucose homeostasis. Hepatic deletion of miR-33 also increased circulating HDL-C levels which is consistent with the notion that ABCA1 is essential for RCT and is repressed by miR-33 [58].…”

miR‐33 in cardiometabolic diseases: lessons learned from novel animal models and approaches

“…Bone marrow transplant from miR-33-deficient animals into LDLR knockout mice did not result in the obesity or metabolic dysfunction observed in miR-33/LDLR double knockout animals, suggesting that macrophages and other hematopoietic cells were not responsible for driving this phenotype (Price et al, 2017). Consistent with this, characterization of macrophage-specific miR-33 conditional knockout mice also did not reveal any differences in body weight or circulating lipids under hyperlipidemic conditions (Price et al, 2021). In addition to demonstrating that neither direct effects of the liver, adipose tissue, or macrophages contribute substantially to the obesity phenotype of whole-body miR-33 knockout mice, this work also indicates that signaling from these peripheral tissues is not responsible for promoting the increased feeding that was observed.…”

“…Dissecting the contribution of miR-33 in different metabolic tissues in regulating glucose homeostasis and obesity Considering the dramatic metabolic alterations in miR-33-deficient animals and the important implications of this for the potential use of miR-33 inhibitors to treat atherosclerosis and other conditions, our recent work has sought to determine what organs and/or cell types are primarily responsible for driving these metabolic changes. Development of conditional miR-33 knockout models has facilitated exploration of the specific roles of miR-33 in key metabolic tissues (Price et al, 2021). As the work of Horie et al indicated that changes in hepatic lipid metabolism may be responsible for driving the metabolic dysfunction of miR-33-deficient animals (Horie et al, 2013), our initial efforts focused on characterizing the impact of hepatocyte-specific miR-33 deficiency, by crossing conditional miR-33 knockout animals with mice expressing Albumin-Cre.…”

“…Importantly, mice lacking miR‐33 only in the liver did not demonstrate the adverse metabolic effects observed in global miR‐33 knockout models. However, despite the beneficial changes in lipid metabolism, loss of miR‐33 in the liver did not have any impact on atherosclerotic plaque size (Price et al, 2021). This is likely due to the fact that SREBP2 and miR‐33 are strongly downregulated in the liver under hyperlipidemic conditions (Rayner et al, 2010; Nishino et al, 2018) and under these conditions liver‐specific miR‐33 knockout mice no longer show any differences in circulating HDL‐C or total cholesterol (Price et al, 2021).…”

“…However, despite the beneficial changes in lipid metabolism, loss of miR‐33 in the liver did not have any impact on atherosclerotic plaque size (Price et al, 2021). This is likely due to the fact that SREBP2 and miR‐33 are strongly downregulated in the liver under hyperlipidemic conditions (Rayner et al, 2010; Nishino et al, 2018) and under these conditions liver‐specific miR‐33 knockout mice no longer show any differences in circulating HDL‐C or total cholesterol (Price et al, 2021). These findings support the conclusion that in rodents the pro‐atherogenic effects of miR‐33 are primarily due to direct effects on macrophages within the atherosclerotic plaque, but also indicate that detrimental effects of inhibition of miR‐33 in the liver are unlikely.…”