Qushi Huayu decoction attenuated hepatic lipid accumulation via JAK2/STAT3/CPT-1A-related fatty acid β-oxidation in mice with non-alcoholic steatohepatitis

Abstract

Context Qushi Huayu decoction (QHD) has been clinically used for treating non-alcoholic steatohepatits (NASH). However, little is known about the effect of QHD on fatty acid β-oxidation (FAO)-dependent lipid consumption. Objective To investigate the mechanism of QHD on FAO-related hepatic lipid accumulation. Materials and methods Male C57BL/6J mice were randomly divided into 5 groups ( n = 8): normal diet and drinking water (CON), high-fat and high-carbohydrate diet (HFHC), QHD-L (2.875 g/kg), QHD-H (11.5 g/kg) and obeticholic acid (OCA) (10 mg/kg/day) groups. All mice freely consumed an appropriate diet for 18 weeks, and QHD was orally administered in the last 6 weeks. Measurements of general condition, hepatic histopathology, and JAK2/STAT3 signalling pathway were taken. Results QHD significantly improved NASH in mice, as reflected by improving serum glucolipid metabolism, decreasing enzymes activities, reducing hepatic triglyceride (HFHC: 70.07 ± 2.81 mg/g; QHD-H: 34.06 ± 5.74 mg/g) and ameliorating hepatic steatosis, inflammation in pathology. Further, both the mRNA and protein level of hepatic CPT-1A ( p < 0.05), a rate-limiting enzyme of FAO, increased drastically following QHD treatment. Meanwhile, the content of hepatic ATP ( p < 0.05) increased significantly after treatment with QHD. Further mechanistic results revealed that both the total protein and nuclear p-STAT3 in the liver were significantly down-regulated after QHD treatment. The protein level of hepatic p-JAK2 was significantly inhibited by QHD ( p < 0.05 or p < 0.01). Conclusions QHD could attenuate lipid accumulation by increasing JAK2/STAT3/CPT-1A-related FAO, which provides a scientific basis for the clinical application of QHD in treating NASH.

Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway

“…Inhibition of Notch signaling can regulate lipid metabolism and improve nonalcoholic fatty liver disease. The pro-fibrotic effect of Notch signaling is related to impaired lipid metabolism of renal tubular epithelial cells [ 24 ], and regulation of stat3 signaling can promote the oxidation of fatty acids and improve lipid accumulation in liver [ 27 ]. In this study, we hypothesized that CA could inhibit Notch1 and stat3 signaling, and that CA might regulate Notch1 and stat3 signaling to inhibit renal lipid accumulation and renal fibrosis induced by high glucose and high lipid in HK2 cells.…”

“…There is evidence that inhibiting stat3 activation in STZ-induced DKD can prevent the progression of fibrosis [ 26 ] and inhibited Stat3 signal can promote fatty acid oxidation and thus improve lipid accumulation in the liver. [ 27 ]. Moreover, cross-talk between Notch-Hes and stat3 signaling has also been reported [ 28 ].…”

Qushi Huayu decoction ameliorates non-alcoholic fatty liver disease in rats by modulating gut microbiota and serum lipids

“…QHD has been clinically used for NAFLD treatment in China for decades. In recent studies, the mechanism of QHD in NAFLD is related to the biological functions of reducing oxidative stress, regulating intestinal microbiota, regulating body metabolism and signaling pathways, promoting browning of white adipose tissue, and inhibiting lipogenesis ( 9 , 12 , 14 , 15 , 34 , 35 ). Furthermore, it has been reported that many bioactive components of QHD have significant anti-NAFLD activities.…”

“…As a clinical empirical prescription, Qushi Huayu decoction (QHD) has been used in the intervention of NAFLD in China for several decades ( 9 , 10 ). The efficacy of QHD has been demonstrated in several models of NAFLD in vivo and in vitro ( 9 , 11 – 13 ), and the mechanisms include regulation of branched-chain amino acid metabolism disorder, upregulation of AMPK/SIRT1/UCP-1 signaling pathway ( 14 ), modulation of fatty acid β-oxidation ( 15 ), regulation of gut microbiota composition, and protection of intestinal tight junctions ( 16 ).…”