Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.

The maintenance of cholesterol homeostasis is crucial for normal function at both the cellular and organismal levels. Two integral membrane proteins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and Scap, are key targets of a complex feedback regulatory system that operates to ensure cholesterol homeostasis. HMGCR catalyzes the rate-limiting step in the transformation of the 2-carbon precursor acetate to 27-carbon cholesterol. Scap mediates proteolytic activation of sterol regulatory element-binding protein-2 (SREBP-2), a membrane-bound transcription factor that controls expression of genes involved in the synthesis and uptake of cholesterol. Sterol accumulation triggers binding of HMGCR to endoplasmic reticulum (ER)-localized Insig proteins, leading to the enzyme's ubiquitination and proteasome-mediated ER-associated degradation (ERAD). Sterols also induce binding of Insigs to Scap, which leads to sequestration of Scap and its bound SREBP-2 in the ER, thereby preventing proteolytic activation of SREBP-2 in the Golgi. The oxygenated cholesterol derivative 25-hydroxycholesterol (25HC) and the methylated cholesterol synthesis intermediate 24,25-dihydrolanosterol (DHL) differentially modulate HMGCR and Scap. While both sterols promote binding of HMGCR to Insigs for ubiquitination and subsequent ERAD, only 25HC inhibits the Scap-mediated proteolytic activation of SREBP-2. We showed previously that 1,1-bisphosphonate esters mimic DHL, accelerating ERAD of HMGCR while sparing SREBP-2 activation. Building on these results, our current studies reveal specific, Insig-independent photoaffinity labeling of HMGCR by photoactivatable derivatives of the 1,1-bisphosphonate ester SRP-3042 and 25HC. These findings disclose a direct sterol binding mechanism as the trigger that initiates the HMGCR ERAD pathway, providing valuable insights into the intricate mechanisms that govern cholesterol homeostasis.

Effects of a virtual reality-based motivational reinforcement + desensitization intervention program on psychological craving and addiction memory in female MA-dependent young adults.

Objectives: The aim of this study was to explore the effects of a virtual reality (VR)-based motivational reinforcement + desensitization intervention program on psychological craving and addiction memory in female methamphetamine (MA)-dependent young adults. Methods: We recruited 60 female MA-dependent young adults in a compulsory isolation drug rehabilitation facility in Sichuan Province, and randomly assigned them to intervention (mean age = 23.24 ± 2.06) and control groups (mean age = 23.33 ± 2.09). The intervention group received a VR-based motivational enhancement + desensitization intervention (total of eight sessions over a 4-week period), while the control group received regular detoxification management during the same period. Assessments were conducted before, immediately after, and 1 month after the intervention, with a visual analogue scale (VAS) being used to assess subjective craving, electronic sphygmomanometer employed to measure physiological parameters, and the Addiction Memory Intensity Scale (AMIS) applied to assess addiction memory intensity. Results: Generalized estimating equation analysis showed significant main effects of group on changes in heart rate difference, systolic blood pressure difference, VAS and AMIS scores (all p < 0.01), and a significant time main effect on changes in diastolic blood pressure difference, VAS and AMIS scores (all p < 0.01), and a significant group × time interaction effect on changes in the difference values of three physiological parameters, VAS and AMIS scores (p < 0.01 or p < 0.05). After the intervention, the differences in three physiological parameters, and the VAS and AMIS scores, were significantly lower in the intervention than in the control group (all p < 0.05), and the difference between the two groups remained significant 1 month after the end of the intervention (both p < 0.01). VAS scores, heart rate difference, and diastolic blood pressure difference in the intervention group were significantly lower than baseline scores, both at the end of the intervention and 1 month thereafter (all p < 0.01); the systolic blood pressure difference in the intervention group was significantly lower at the end of the intervention than at baseline (p < 0.05); AMIS scores in the intervention group were significantly lower than the baseline scores 1 month after the end of the intervention (p < 0.01). Conclusion: Our VR-based motivational reinforcement + desensitization intervention program can effectively reduce psychological craving and physiological reactivity for drugs, and the intensity of addictive memories in female MA-dependent young adults, even after 1 month.