Statins are inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis, and have been clinically used to treat cardiovascular disease. However, a paradoxical increase of reductase protein following statin treatment may attenuate the effect and increase the side effects. Here we present a previously unexplored strategy to alleviate statin-induced reductase accumulation by inducing its degradation. Inspired by the observations that cholesterol intermediates trigger reductase degradation, we identify a potent degrader, namely Cmpd 81, through structure–activity relationship analysis of sterol analogs. Cmpd 81 stimulates ubiquitination and degradation of reductase in an Insig-dependent manner, thus dramatically reducing protein accumulation induced by various statins. Cmpd 81 can act alone or synergistically with statin to lower cholesterol and reduce atherosclerotic plaques in mice. Collectively, our work suggests that inducing reductase degradation by Cmpd 81 or similar chemicals alone or in combination with statin therapy can be a promising strategy for treating cardiovascular disease.

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Background: High blood cholesterol accelerates the progression of atherosclerosis that is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis that results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease (ASCVD). Methods: Low-density lipoprotein (LDL) receptor (LDLR) was used as the bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK, encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo , we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice, as well as knocked Klkb1 down using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and PCSK9 inhibition was evaluated as well. We also applied the anti-PK neutralizing antibody that blocked PK and LDLR interaction to mice. Mice lacking both PK and Apolipoprotein e ( Klkb1 -/- Apoe -/- ) were generated to assess the role of PK in atherosclerosis. Results: PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of PCSK9 with Evolocumab further decreased plasma LDL cholesterol levels in Klkb1 -deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed down the progression of atherosclerosis in mice on Apoe -deficient background. Conclusions: PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat ASCVD.

Objective: A high level of LDL-C (low-density lipoprotein cholesterol) is a major risk factor for cardiovascular disease. The E3 ubiquitin ligase named IDOL (inducible degrader of the LDLR [LDL receptor]; also known as MYLIP [myosin regulatory light chain interacting protein]) mediates degradation of LDLR through ubiquitinating its C-terminal tail. But the expression profile of IDOL differs greatly in the livers of mice and humans. Whether IDOL is able to regulate LDL-C levels in humans remains to be determined. Approach and Results: By using whole-exome sequencing, we identified a nonsynonymous variant rs149696224 in the IDOL gene that causes a G51S (Gly-to-Ser substitution at the amino acid site 51) from a Chinese Uygur family. Large cohort analysis revealed IDOL G51S carriers (+/G51S) displayed significantly higher LDL-C levels. Mechanistically, the G51S mutation stabilized IDOL protein by inhibiting its dimerization and preventing self-ubiquitination and subsequent proteasomal degradation. IDOL(G51S) exhibited a stronger ability to promote ubiquitination and degradation of LDLR. Adeno-associated virus-mediated expression of IDOL(G51S) in mouse liver decreased hepatic LDLR and increased serum levels of LDL-C, total cholesterol, and triglyceride. Conclusions: Our study demonstrates that IDOL(G51S) is a gain-of-function variant responsible for high LDL-C in both humans and mice. These results suggest that IDOL is a key player regulating cholesterol level in humans.

The changes that COVID-19 pandemic has brought upon the world are unprecedented. Its impact on students’ learning is equally profound, making it critical to heed students’ academic achievement effects that may derive from these alterations. Therefore, the present study explored an integrative model of mental health, self-regulated learning and academic achievement among adolescents during the pandemic. Participants were 1001 senior high school students ( M age = 17.00, SD age = 0.78, 48.7% female) from China. Results showed that the degree to which students were mentally healthy was not significantly related to academic achievement, whereas academic achievement and mental health were positively associated with self-regulated learning. Following structural equation modelling analysis, the effect of mental health on academic achievement was fully mediated by self-regulated learning. Taken together, the findings emphasised the necessity of developing self-regulated learning strategies during public health emergencies and have clinical and educational implications for planning psychological interventions in order to improve mental health and academic performance as well.