11β-HSD1 Inhibitor Alleviates Non-Alcoholic Fatty Liver Disease by Activating the AMPK/SIRT1 Signaling Pathway

Abstract

We investigated the effect of an 11β-HSD1 inhibitor (H8) on hepatic steatosis and its mechanism of action. Although H8, a curcumin derivative, has been shown to alleviate insulin resistance, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. Rats were fed a high-fat diet (HFD) for 8 weeks, intraperitoneally injected with streptozotocin (STZ) to induce NAFLD, and, then, treated with H8 (3 or 6 mg/kg/day) or curcumin (6 mg/kg/day) for 4 weeks, to evaluate the effects of H8 on NAFLD. H8 significantly alleviated HFD+STZ-induced lipid accumulation, fibrosis, and inflammation as well as improved liver function. Moreover, 11β-HSD1 overexpression was established by transfecting animals and HepG2 cells with lentivirus, carrying the 11β-HSD1 gene, to confirm that H8 improved NAFLD, by reducing 11β-HSD1. An AMP-activated protein kinase (AMPK) inhibitor (Compound C, 10 μM for 2 h) was used to confirm that H8 increased AMPK, by inhibiting 11β-HSD1, thereby restoring lipid metabolic homeostasis. A silencing-related enzyme 1 (SIRT1) inhibitor (EX572, 10 μM for 4 h) and a SIRT1 activator (SRT1720, 1 μM for 4 h) were used to confirm that H8 exerted anti-inflammatory effects, by elevating SIRT1 expression. Our findings demonstrate that H8 alleviates hepatic steatosis, by inhibiting 11β-HSD1, which activates the AMPK/SIRT1 signaling pathway.

Molecular Mechanism of Curcumin Derivative on YAP Pathway against Ovarian Cancer

“…Some studies have found that CUR can prevent tumor angiogenesis and cell proliferation, induce cancer cell apoptosis, downregulate epidermal growth factor receptor (EGFR) activity and human epidermal growth factor receptor 2 (HER2) expression levels, downregulate nuclear transcription factor, inhibit the activation of the STAT3 signaling pathway, downregulate the expression level of cyclooxygenase 2 (COX-2), and reduce the synthesis level of MMP9 and inducible nitric oxide synthase (iNOS), thus exerting its antitumor effect through multiple pathways [ 14 , 15 ]. However, the application of CUR is constrained by its low water solubility, ease of aqueous solution hydrolysis, clear first-pass elimination effect and low bioavailability [ 16 ]. Obtaining CUR analogs or derivatives through molecular structure modification can well improve the bioavailability of drugs [ 17 ].…”

Four‐Arm Polymer‐Guided Formation of Curcumin‐Loaded Flower‐Like Porous Microspheres as Injectable Cell Carriers for Diabetic Wound Healing

“…After 3 weeks of treatment, all mice were euthanized, and their blood and primary organs were collected. [ 85 ] The main organs were embedded in paraffin and stained with hematoxylin and eosin for pathomorphological assessment.…”

“…Protein expression was quantified and normalized to β‐Actin expression (1:1000, Cell Signaling, Shanghai, China). [ 85 ]…”

“…Compatibility of BMSC@FPM in Mice: As described in previous studies, [85] mice were maintained at 22 °C under a 12-h light/dark cycle. Approximately 2-3 × 10 5 cells were used in each group.…”

New Insights into Baicalein’s Effect on Chlorpyrifos-Induced Liver Injury in Carp: Involving Macrophage Polarization and Pyropto sis

“…The AMP-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor γ coactivator 1α (pGC-1α) pathway is closely associated with cellular energy metabolism, glucose metabolism, and oxidative damage. − AMPK is a serine/threonine protein kinase that is activated primarily by regulation in response to cellular energy deficiency. Activated AMPK then sequentially activates SIRT1 and pGC-1α, which play key regulatory roles in mitochondrial biosynthesis, mitochondrial dynamics, energy metabolism, and resistance to oxidative stress. − Mitochondrial dynamics, including mitochondrial fusion and fission, along with mitochondrial biosynthesis maintain the normal biological function of mitochondria.…”