| Study (year) | Model/system | Perturbation/condition | Key quantitative results (include numeric values, fold changes, doses, time) | Interpretation for HMGCS2 function | URL/DOI |
|---|---|---|---|---|---|
| Zhou et al. (2023) | Liver-specific Hmgcs2 knockout (LKO) mice; WT controls; BRL hepatocyte cells | 24 h fasting; hepatocyte Hmgcs2 deletion | WT mice showed an approximately **2-fold increase** in blood **β-hydroxybutyrate** after **24 h fasting**, whereas LKO mice **failed to develop hyperketonemia**. Hepatic **CD36** was **~4-fold higher** in LKO versus WT. In fasted animals, circulating triglyceride and free fatty acid increases seen in WT were **nearly abolished** in LKO, while hepatic triglyceride/FFA accumulation and serum ALT/AST were markedly increased in LKO. In BRL cells, starvation medium increased **HMGCS2** and **CD36** protein with increased lipid accumulation. (pqac-00000004) | Hepatic HMGCS2 is required for fasting-induced ketogenesis and protects liver lipid homeostasis; loss of HMGCS2 diverts fatty-acid carbon toward hepatic lipid accumulation/injury rather than ketone production. | https://doi.org/10.1016/j.gendis.2022.08.004 |
| Bass et al. (2024) | Global and intestinal-conditional Hmgcs2 knockout mice; DSS colitis model; human IBD transcriptomic datasets | Basal vs fasting ketones; intestinal/colonic Hmgcs2 deletion; inflammatory bowel disease context | In inflamed human colonic tissues, **HMGCS2 mRNA decreased by >75%** (**P < 0.001**). CRISPR global Hmgcs2 deletion caused **50–60% postnatal mortality by 30 days**, with **3–4-fold increased liver weight** and markedly reduced fasting-induced blood ketones. Conditional intestinal Hmgcs2 knockout mice had **lower fasting blood ketones** than controls. The paper also notes physiologic circulating ketone ranges of **~0.1 mM fed** and up to **6–8 mM** with prolonged fasting/diabetes. (pqac-00000005, pqac-00000007) | Hmgcs2 is not only hepatic but also functionally important in colon/cecum; intestinal ketogenesis contributes to circulating ketones and mucosal protection, while loss of Hmgcs2 predisposes to colitis and systemic inflammation. | https://doi.org/10.1042/bcj20230403 |
| Li et al. (2024) | AML12 hepatocytes; primary mouse hepatocytes; C57BL/6J mice; transplant patients | Tacrolimus exposure; hepatic HMGCS2 rescue by AAV8-TBG-HMGCS2 | Tacrolimus was given at **10 ng/mL** in vitro (with **0/10/20 ng/mL** dose groups), with **250 μM palmitic acid for 48 h** in hepatocyte experiments; mice received tacrolimus **2.5 mg·kg⁻¹·day⁻¹ for 10 weeks**. Tacrolimus markedly decreased **HMGCS2** expression and ketogenesis, increased acetyl-CoA accumulation and mitochondrial protein acetylation, and reduced mitochondrial membrane potential/OCR. Liver-directed **AAV8-TBG-HMGCS2** restored HMGCS2 protein, ketone production, FAO-linked mitochondrial function, and reversed hepatic lipid deposition. Tacrolimus also increased **FoxO1 Ser256 phosphorylation** and reduced FoxO1 occupancy at the Hmgcs2 promoter. (pqac-00000006, pqac-00000008) | Drug-induced suppression of HMGCS2 is sufficient to impair ketogenesis and promote hepatic steatosis; restoring HMGCS2 function can reverse tacrolimus-associated lipid dysregulation, supporting HMGCS2 as a therapeutic node. | https://doi.org/10.1038/s41401-024-01300-0 |
| Asif (2022) | Chow-fed vs high-fat-diet NAFLD mice | 24 h fasting in healthy vs NAFLD mice after chronic HFD | In healthy mice, plasma **β-hydroxybutyrate reached 1.3 ± 0.06 mmol/L** after **24 h fasting**; NAFLD mice failed to raise ketones beyond **0.8 ± 0.03 mmol/L**. Fasting induced hepatic **Hmgcs2 mRNA 2.1-fold** (**P < 0.001**) and protein **2.3-fold** (**P = 0.015**) in healthy mice, but only a **1.6-fold** mRNA response in NAFLD with no comparable protein increase. (pqac-00000010) | Impaired HMGCS2 induction is a measurable feature of diet-induced NAFLD and likely contributes to defective fasting ketogenesis and hepatic metabolic inflexibility. | https://doi.org/10.20381/ruor-27363 |
| Asif (2022) | Hmgcs2-KO, Hmgcs2-HET, HMGCS2-overexpressing mice; HepG2 cells | Loss- or gain-of-function of HMGCS2; HFD or developmental high-fat exposure | HMGCS2 overexpression caused a **<1 mM** rise in plasma ketones yet significantly reduced plasma glucose and hepatic fat; early weaning at **postnatal day 14 (p14)** versus normal **~p21** reduced neonatal liver fat in models where Hmgcs2 loss predisposed to steatosis. Long-term HFD (**32 weeks**) reduced fasting ketone output and hepatic Hmgcs2 expression. (pqac-00000009, pqac-00000011) | Even modest augmentation of HMGCS2-driven ketogenesis can improve hepatic metabolic phenotypes; conversely, partial or complete Hmgcs2 deficiency increases susceptibility to fatty liver. | https://doi.org/10.20381/ruor-27363 |
| Suresh et al. (2025 review summarizing quantitative physiology) | Human/animal ketone physiology and HMGCS2-regulated states | Baseline, fasting, exercise, prolonged fasting; diabetes/SGLT2i context | Typical circulating ketone concentrations are reported as **0.05–0.4 mM** at baseline, **1–2 mM** with fasting/exercise, and **6–8 mM** after prolonged fasting; these ranges contextualize HMGCS2-controlled ketogenesis in health and disease. The review also notes hymeglusin as a potent HMGCS inhibitor with **IC50 ~0.1 μM**. (pqac-00000023, pqac-00000029) | These quantitative ranges help interpret when HMGCS2 activity is physiologic versus potentially pathologic, and underscore the enzyme’s tractability for pharmacologic modulation. | https://doi.org/10.3390/biom15040580 |


*Table: This table summarizes numeric findings from recent and foundational studies relevant to HMGCS2/Hmgcs2 function, regulation, and phenotype. It highlights effect sizes, doses, and time courses that are most useful for functional annotation and translational interpretation.*