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.