Casz1 and Znf101/Zfp961 differentially regulate apolipoproteins A1 and B, alter plasma lipoproteins, and reduce atherosclerosis
Abulaish Ansari, … , Antoine Rimbert, M. Mahmood Hussain
Abulaish Ansari, … , Antoine Rimbert, M. Mahmood Hussain
Published January 9, 2025
Citation Information: JCI Insight. 2025;10(1):e182260. https://doi.org/10.1172/jci.insight.182260.
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Research Article Vascular biology

Casz1 and Znf101/Zfp961 differentially regulate apolipoproteins A1 and B, alter plasma lipoproteins, and reduce atherosclerosis

Abstract

High apolipoprotein B–containing (apoB-containing) low-density lipoproteins (LDLs) and low apoA1–containing high-density lipoproteins (HDLs) are associated with atherosclerotic cardiovascular diseases. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both significantly decreases apoB and increases apoA1 expression by inducing mRNA degradation of 2 different transcription factors, Znf101 and Casz1. We found that Znf101 enhances apoB expression, while Casz1 represses apoA1 expression. The hepatic knockdown of Casz1 in mice increased plasma apoA1, HDL, and cholesterol efflux capacity. The hepatic knockdown of Zfp961, an ortholog of Znf101, reduced lipogenesis and production of triglyceride-rich lipoproteins and atherosclerosis, without causing hepatic lipid accumulation. This study identifies hepatic Znf101/Zfp961 and Casz1 as potential therapeutic targets to alter plasma lipoproteins and reduce atherosclerosis without causing liver steatosis.

Authors

Abulaish Ansari, Pradeep Kumar Yadav, Liye Zhou, Binu Prakash, Laraib Ijaz, Amanda Christiano, Sameer Ahmad, Antoine Rimbert, M. Mahmood Hussain

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Figure 4

Hepatic KD of Casz1 and Zfp961 alters plasma lipoproteins.

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Hepatic KD of Casz1 and Zfp961 alters plasma lipoproteins. Mice (C57BL/6...
Mice (C57BL/6J, female, 2.5 months old) were transduced with AAV8 (2.5 × 1011 gc/mouse) expressing shControl (shCtrl, n = 4), shCasz1 (n = 4), shZfp961 (n = 4), or [sh(C+Z), n = 5], and fed a Western diet. (A–D) After 6 weeks, livers were collected to measure mRNA levels in triplicate. (E and F) Plasma was collected from fasting mice to measure triglyceride and cholesterol (E) in technical duplicate, and subjected to precipitation using polyethylene glycol to measure cholesterol in HDL and non-HDL fractions (F) in triplicate. (G) Plasma (200 μL) obtained at the end of the study was subjected to FPLC, and triglyceride and cholesterol were measured in different fractions. (H) Mice were gavaged with olive oil (100 μL) after overnight fasting. Plasma was collected at different times to measure triglycerides in duplicate. Increases in plasma triglyceride were plotted as percentage of initial values before gavage. (I) Mice were fasted overnight prior to blood collection. Mice were injected intraperitoneally with poloxamer 407 (1.5 mg/g). Blood was collected to measure triglycerides (left) in triplicate. Data between 2 and 4 hours were used to calculate production rates (right). *P < 0.05; **P < 0.01, ***P < 0.001; ****P < 0.0001 by ordinary 1-way ANOVA pairwise multiple comparisons, where different groups were compared with control.