TABLE 1.
The summary of preclinical studies of celastrol in HFD induced MAFLD models.
| Experimental model used | Model inducer | Dosage and drug-delivery way | Drug treatment period | Phenotype and mechanism | Reference |
|---|---|---|---|---|---|
| Wild type animal models | |||||
| Male Sprague–Dawley rats | HFD | 1 mg/kg/day, 3 mg/kg/day, and 9 mg/kg/day by oral administration | 6 weeks | Promoted weight loss and lipid metabolism, attenuated oxidative injury through improving ABCA1 and antioxidant enzymes activities, reducing NADPH oxidase activity | Wang et al. (2014) |
| HFD for 11 weeks | 500 μg/kg/day by oral administration | 3 weeks | Decreased body weight and lipid accumulation in liver, promoted energy expenditure by increasing ratio of Bacteroidetes to Firmicutes rather than food intake, leptin signaling pathway, gut microbiota homeostasis | Hu et al. (2020) | |
| HFD for 17 weeks | 1 mg/kg/day, 3 mg/kg/day mixed with drinking water | 8 weeks | Reduced body weight, alleviated inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle by upregulation of AMPK/SIRT1 signaling pathways | Abu Bakar et al. (2020) | |
| Male C57BL/6J mice | HFD for16-20 weeks | 100 μg/kg/day by i.p injection, or 10 mg/kg/day by oral administration | 3 weeks | Improved weight loss and glucose homeostasis by reducing food consumption and ER stress in hypothalamus | Liu et al. (2015) |
| NCD or HFD for 9 weeks | 100 μg/kg/day or 500 μg/kg/day by i.p injection | 24 days | Reduced body weight and fat mass by decreased food intake, improved metabolism by increased homeostatic regulation of energy balance related gene expressions in the hypothalamus | Saito et al. (2019) | |
| HFD for 8 weeks | 1 mg/kg/day, 3 mg/kg/day mixed with food | 3 weeks | Enhanced energy expenditure, and mitochondrial function in fat and muscle by activated HSF1-PGC1α axis | Ma et al. (2015) | |
| HFD for 14 weeks | 200 μg/kg/every 2 days by i.p injection | 4 weeks | Inhibited lipid synthesis by downregulation of Srebp-1c expression, reduced oxidative stress and inflammation by enhanced the phosphorylation of hepatic AMPKα and Sirt1 | Zhang et al. (2017a) | |
| HFD for 12 weeks | 100 μg/kg/day by i.p injection | 2 weeks | Suppressed hepatic inflammation and immune cell accumulation by reducing expression and production of IL-1β and IL-6 | Hu et al. (2017) | |
| HFD for 16 weeks | 100 μg/kg/day by i.p injection | 8 weeks | Attenuated inflammation and insulin resistance by inhibition of TLR4/NF-κB | Zhang et al. (2018) | |
| HFD for 32 weeks | 100 μg/kg/day by i.p injection | 6 days | Promoted weight loss through hypoplasia and activation of leptin-STAT3 signaling in elder mice | Pfuhlmann et al. (2018) | |
| HFD for 8–12 weeks | 100 μg/kg/day by i.p injection | 10 days | Lowered body weight by inhibition of PTP1B and TCPTP in hypothalamus | Kyriakou et al. (2018) | |
| HFD for16-20 weeks | 100 μg/kg/day by i.p injection | 4 days | Celastrol’s anti-obesity effects was not dependent on LCN2 | Feng et al. (2019a) | |
| HFD for 16 weeks | 0.1 mg/kg/day by i.p injection | 21 days | Suppressed gluconeogesis by activating CREB/PGC-1α pathway | Fang et al. (2019) | |
| HFD for 12 weeks | 150 μg/kg, 300 μg/kg by i.p injection | 3 weeks | Reduced weight gain without affecting food intake, ameliorated metabolic disorder and hepatic inflammation by inhibition of TLR3/NLRP3 inflammasome | Yang et al. (2021) | |
| HFD for 6 weeks | 3 mg/kg/day was mixed with food | 24 days | Prevented intestinal lipid absorption by downregulation of CD36, FATP2, FATP4 | Hua et al. (2021) | |
| HFD for 12 weeks | 50 μg/kg/day, 100 μg/kg/day, 200 μg/kg/day by i.p injection | 12 weeks | Attenuated inflammation through the suppression of MMP-2 and MMP-9 | Ouyang et al. (2021) | |
| HFD for 16 weeks | 0.75 mg/kg/day,1.5 mg/kg/day,3 mg/kg/day by oral administration | 25 days | Reduced body weight gain, insulin resistance, hepatic steatosis, and inflammation by inhibition of CAP1‒resistin interaction, PKA‒NF-kB pathway | Zhu Y. et al. (2021) | |
| Male C57BL/6 N mice | HFD for 12 weeks | 5 mg/kg/day and 7.5 mg/kg/day mixed with food | 3 weeks | Prevented M1 macrophage polarization, inflammation, and insulin resistance via regulating Nrf2/HO‐1, MAPK signal, and NF-κB pathway | Luo et al. (2017) |
| HFD for12 weeks | 5 mg/kg/day or 7.5 mg/kg/day by oral administration | 3 weeks | Reduced body weight and fat mass inhibited inflammatory response by downregulation of expression of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) and enhanced expression of macrophage M2 biomarkers (e.g., Arg-1, IL-10) | Zhao et al. (2019a) | |
| Genetic deficency animal models | |||||
| Lepdb mice | NCD | 100 μg/kg/day by i.p. injection, or 10 mg/kg/day by oral administration | 3 weeks | No significant change of body weight | Liu et al. (2015) |
| 100 μg/kg/day by subcutaneous injection | 6 days | Pfuhlmann et al. (2018) | |||
| 100 μg/kg by i.p. injection | 3 weeks | Feng et al. (2019b) | |||
| 100 μg/kg by i.p. injection | 4 days | Feng et al. (2019a) | |||
| 0.1 mg/kg/day by i.p. injection for 10 days, then 0.5 mg/kg by i.p.injection for 15 days | 25 days | Body weight slightly reduced | (Saito et al., 2019)] | ||
| Lep−/+ rats and Lep−/− rats | HFD for 17 weeks | 0.5 mg/kg/day or 1 mg/kg/day by oral administration | 3 weeks | 1,000 μg/kg celastrol decreased the BW of Lep−/+ rats not Lep−/− rats | Hu et al. (2020) |
| Lepob mice | NCD for 6 or 14 weeks | 100 μg/kg/day by subcutaneous injection | 6 days | Promoted weight loss in young Lepob mice not old Lepob mice | Liu et al. (2015) |
| HSF1 −/− Mice | HFD for 4 weeks | 3 mg/kg/day mixed with powdered chow | 4 weeks | Had no effects on body weight and energy consumption | Ma et al. (2015) |
| Liver specific Sirt1 KO mice | HFD for 14 weeks | 200 μg/kg/every 2 days by i.p.injection | 4 weeks | Reduced food intake and increased the hepatic lipid accumulation by inhibited phosphorylation of AMPKα and hepatic LKB1 expression | Zhang et al. (2017a) |
| Nur77 −/−mice | HFD for 17 weeks | 0.1 mg/kg/day by i.p injection | 2 weeks | Mild reduced the body weight and anti-inflammation effects attenuated | Hu et al. (2017) |
| Global PTP1B KO mice | NCD or HFD for 10 weeks | 0.1 mg/kg/day by i.p injection | 7 days | Induced weight loss both in NCD and HFD PTP1B mice, reduction of fat and lean mass is owing to weight loss of HFD PTP1B mice not for NCD mice | Pfuhlmann et al. (2018) |
| UCP1 KO mice | HFD for 20 weeks | 100 μg/kg/day by subcutaneous injection | 6 days | Decreased body weight and food intake by fat mass loss | Pfuhlmann et al. (2018) |
| IL1R1−/− mice | HFD for 20 weeks | 100 μg/kg/day by i.p. injection | 3 weeks | No change of body weight, fat mass, and food intake | Zhao et al. (2019a) |
| Lcn2−/− mice | NCD or HFD for 16-20 weeks | 100 μg/kg/day by i.p. injection | 3 weeks | Reduced body weight and fat mass without affected food intake in NCD Lcn2−/− mice, inhibited hepatosteatosis, and metabolic disorder induce by HFD in Lcn2−/− mice | Feng et al. (2019a) |
| ApoE−/- mice | NCD or HFD for 12 weeks | 100 μg/kg/day by oral administration | 12 weeks | Alleviated inflammatory reaction in apoE−/- mice fed with HFD | Zhu Y. et al. (2021) |
| Melanocortin 4 receptor (MC4R)-null mice | NCD | 0.1 mg/kg/day by i.p injection for 10 days, then 0.5 mg/kg/day by i.p injection for 15 days | 25 days | Reduced body weight, food intake, fat and lean mass, enhanced energy expenditure by upregulation of adrenergic receptor and PRDM16 without affecting UCP-1 and PGC-1α | Saito et al. (2019) |
| HnRNPA1 deficency/overexpression mice | NCD | 2 mg/kg/day by gavage administration | 12 days | Inhibited energy expenditure and abrogated weight loss effects in HnRNPA1 overexpression mice | Zhu C. et al. (2021) |
| Other model | |||||
| Young (4–6 month) and Old (18–22 month) male mice | NCD | 100–200 μg/kg/day by i.p. injection | 4–6 days | Promoted weight and lean mass loss by lowering food intake in aged mice, but not in young controls | Chellappa et al. (2019) |
HFE, high fat emulsion; NCD, normal chow diet; HFD, high fat diet; ABCA1, ATP-binding cassette transporter A1; NADPH, nicotinamide adenine dinucleotide phosphate; AMPK, Adenosine 5‘-monophosphate (AMP)-activated protein kinase; SIRT1, sirtuin1; ER, endoplasmic reticulum; HSF1, heat shock factor 1; PGC-1α, Peroxisome proliferator-activated receptor γ coactivator 1α; Srebp-1c, sterol regulatory element binding protein-1c; IL-1β, interleukin-1β; IL-6, interleukin-6; TLR4, Toll-like receptor 4; NF-κB, nuclear factor kappa-B; STAT3, signal transducer and activator of transcription 3; LCN2, lipocalin-2; PTP1B, protein tyrosine phosphatase (PTP) 1B; TCPTP,T-cell PTP; TLR3, Toll-like receptor 3; NLRP3, NOD-like receptor protein 3; CD36, cluster of differentiation 36; FATP2, very-long-chain acyl-CoA, synthetase; FATP4, fatty acid transport protein 4; MMP-2, Matrix metalloproteinase-2; MMP-9, Matrix metalloproteinase-9; CAP1, adenylate cyclase-associated protein 1; PKA, Protein kinase A; NF-kB, nuclear factor kappa B; Nrf2, nuclear respiratory factor 1; HO-1, Heme oxygenase 1; MAPK, mitogen-activated protein kinase; TNF-α, tumor necrosis factor α, iNOS, inducible nitric oxide synthase; Arg-1, arginase-1; IL-10, interleukin-10; Lep, leptin; BW, body weight; LKB1, liver kinase B1; PTP1B, Protein tyrosine phosphatase 1; ApoE, apolipoproteinE; PRDM16, PR, domain-containing 16; UCP-1, Uncoupling protein 1; HnRNPA1,heterogeneous nuclear ribonucleoprotein A1.