Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis

Abstract

Aim. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and if untreated, it may propagate into end-stage liver disease. The classical arm of the renin-angiotensin system (RAS) has a fundamental role in triggering oxidative stress and inflammation, which play potential roles in the pathogenesis of NAFLD. However, the nonclassical alternative axis of RAS, angiotensin- (Ang-) converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor, opposes the actions of the classical arm, mitigates the metabolic dysfunction, and improves hepatic lipid metabolism rendering it a promising protective target against NAFLD. The current study is aimed at investigating the impact of chrysin, a well-known antioxidant flavonoid, on this defensive RAS axis in NAFLD. Methods. Rats were randomly distributed and treated daily for eight weeks as follows: the normal control, chrysin control (50 mg/kg, p.o), NAFLD group (received 20% fructose in drinking water), and treated groups (25 and 50 mg/kg chrysin given orally and concomitantly with fructose). Diminazene aceturate (DIZE) (15 mg/kg, s.c.) was used as a reference ACE2 activator. Key Findings. High fructose induced significant weight gain, hepatocyte degeneration with fat accumulation, and inflammatory cell infiltration (as examined by H&E staining). This was accompanied by a substantial increase in liver enzymes, glucose, circulating and hepatic triglycerides, lipid peroxides, inflammatory cytokines, and Ang II (the main component of classical RAS). At the same time, protein levels of ACE2, Ang (1-7), and Mas receptors were markedly reduced. Chrysin (25 and 50 mg/kg) significantly ameliorated these abnormalities, with a prominent effect of the dose of 50 mg/kg over DIZE and the lower dose in improving ACE2, Ang (1-7), and Mas. Significance. Chrysin is a promising efficient protective remedy against NAFLD; mechanisms include the activation of ACE2/Ang (1-7)/Mas axis.

Identification of lncRNA-miRNA-mRNA Networks in the Lenticular Nucleus Region of the Brain Contributes to Hepatolenticular Degeneration Pathogenesis and Therapy

“…These results indicated that Sp6 may play a role in the pathogenesis of HLD dyskinesia and corneal K-F ring symptoms. The MAS receptor, encoded by the mas1 gene, is observed in microglia and primarily associated with the renin-angiotensin system and the stimulation of anti-inflammatory signaling pathways [ 59 , 60 ]. Microglia have been extensively studied in the context of brain injury as central nervous system guardians [ 61 ].…”

An international multidisciplinary consensus statement on MAFLD and the risk of CVD

“…RAAS activation is implicated in the pathophysiology of both MAFLD and CVD [ 76 ]. RAAS activation in metabolically active tissues can exert pro-inflammatory effects, mainly via angiotensin II, and is associated with multiple dysfunctional cellular processes, leading to hepatic necro-inflammation and fibrosis [ 76 – 78 ]. In a retrospective, territory-wide cohort study of 12,327 patients with NAFLD, the authors found that treatment with RAAS inhibitors was associated with a lower risk of liver-related events, liver cancer and cirrhotic complications, though the indication for use of RAAS inhibitors was for vascular and not liver disease [ 79 ].…”

Myeloid‐Mas Signaling Modulates Pathogenic Crosstalk among MYC+CD63+ Endothelial Cells, MMP12+ Macrophages, and Monocytes in Acetaminophen‐Induced Liver Injury

“…[ 6 ] The beneficial effects of Mas activation have been documented in various diseases. [ 7 , 8 , 9 , 10 ] Our previous research revealed that the activation of Mas effectively attenuates hepatocyte death by enhancing fatty acid oxidation during the early stages of mouse AILI. [ 11 ] However, the role of Mas in the AILI microenvironment remains to be elucidated.…”