Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS

Abstract

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage characterized by abnormal hepatic fat accumulation and inflammatory response. Although the molecular mechanisms responsible for the disease are not yet fully understood, the pathogenesis of NAFLD likely involves multiple signals. The identification of effective therapeutic strategies to target these signals is of utmost importance. Carnosic acid (CA), as a phenolic diterpene with anticancer, anti-bacterial, anti-diabetic and neuroprotective properties, is produced by many species of the Lamiaceae family. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major protein kinase C (PKC) substrate in many different cell types. In the present study, wild-type C57BL/6 and MARCKS-deficient mice were randomly divided into the normal chow- or high-fat (HF) diet-fed groups. The HF diet increased the fasting glucose and insulin levels, and promoted glucose intolerance in the wild-type mice. MARCKS deficiency further upregulated intolerance, fasting glucose and insulin. The HF diet also promoted hepatic steatosis, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, inflammation and lipid accumulation in the wild-type mice. These responses were accelerated in the MARCKS-deficient mice. Importantly, increased inflammation and lipid accumulation were associated with phosphoinositide 3-kinase (PI3K)/AKT, NLR family pyrin domain containing 3 (NLRP3)/nuclear factor-κB (NF-κB) and sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway activation. The mice treated with CA exhibited a significantly improved glucose and insulin tolerance. The production of pro-inflammatory cytokines and lipid accumulation were suppressed by CA. Significantly, MARCKS was reduced in mice fed the HF diet. CA treatment upregulated MARCKS expression compared to the HF group. Furthermore, the activation of the PI3K/AKT, NLRP3/NF-κB and SREBP-1c signaling pathways was inhibited by CA. Taken together, our data suggest that CA suppresses inflammation and lipogenesis in mice fed a HF diet through MARCKS regulation. Thus, CA may be prove to be a useful anti-NAFLD agent.

Ursolic acid alleviates lipid accumulation by activating the AMPK signaling pathway in vivo and in vitro

“…The histopathological analysis of the liver illustrated that HFD treatment exhibited severe liver steatosis and empty lipid vacuoles compared with the NC group, suggesting that HFD treatment induced serious liver fat accumulation in vivo . Moreover, the supplementation of UA significantly alleviated liver steatosis and empty lipid vacuoles compared with the HFD group, which was consistent with a previous study showing that carnosic acid alleviated liver steatosis by decreasing lipid accumulation in HFD‐fad mice (Song et al., 2018). Taken together, these results suggested that UA alleviated liver lipid accumulation in C57BL/6J mice.…”

Immunomodulatory Effects of Diterpenes and Their Derivatives Through NLRP3 Inflammasome Pathway: A Review

“…MyD88 was suggested to be responsible for NF-κB-dependent transcriptional priming ( 64 ). Triptolide ( 30 ), tanshinone IIA ( 34 ), and phorbol 12-myristate 13-acetate ( 43 ) were seen to act through this pathway. TLR4 stimulates NLRP3 inflammasome specific monocytes, which is alone sufficient to cause IL-1β and pro-IL-18 release ( 65 ).…”

“…TLR4 stimulates NLRP3 inflammasome specific monocytes, which is alone sufficient to cause IL-1β and pro-IL-18 release ( 65 ). Triptolide ( 45 ), tanshinone IIA ( 34 ), phorbol 12-myristate 13-acetate ( 43 ), and andrographolide ( 39 ) were seen to act via this pathway. Moreover, p-CREB directly inhibits NF-κB activation by a mechanism that involves hindering the binding of CREB-binding protein to the NF-κB complex, thereby limiting pro-inflammatory responses and suggesting the induction of anti-apoptotic effect, along with proliferation and cell survival ( 66 ).…”

“…It also increased the reduced glutathione (GSH) and superoxide dismutase (SOD) levels and caused a decrease in malondialdehyde (MDA) and iNOS levels in experimental animals ( 42 ). In wild-type C57BL/6 and myristoylated alanine-rich C-kinase substrate (MARCKS) deficient mice, this diterpene has been found to suppress the PI3K/AKT, NLRP3/NF-κB, and sterol regulatory element-binding protein 1 (SREBP-1c) signaling pathways ( 43 ). On the other hand, oridonin (Compound 12) exhibited an anti-inflammatory effect in mice and HEK-293T cells, through the interaction with the cysteine 279 of NLRP3 in NACHT domain, thereby blocking the interaction between NLRP3 and NEK7 and inhibiting NLRP3 inflammasome formation and activation.…”

Potential Therapeutic Benefits of Herbs and Supplements in Patients with NAFLD

“…Ursolic acid’s ability to improve lipotoxicity and lipid homeostasis comes through regulation of PPARα, the AMPK pathway, and reduction of ER stress in hepatic cells [ 87 , 89 , 90 ]. Carnosic acid acts through modulation of hepatic SOD, SIRT1, NF-κB, PI3K/Akt, and SREBP-1c to exert antioxidant, anti-inflammatory, anti-adipogenic, and anti-apoptotic effects [ 88 , 91 , 92 , 93 , 94 ]. Further research on these herbs is necessary to determine their effects on NAFLD patients.…”