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Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS.
- Source :
-
International journal of molecular medicine [Int J Mol Med] 2018 Jul; Vol. 42 (1), pp. 193-207. Date of Electronic Publication: 2018 Mar 27. - Publication Year :
- 2018
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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.
- Subjects :
- Abietanes pharmacology
Animals
Cytokines metabolism
Diet, High-Fat
Feeding Behavior
Glucose metabolism
Homeostasis drug effects
Inflammasomes metabolism
Inflammation Mediators metabolism
Insulin Resistance
Lipogenesis drug effects
Liver drug effects
Liver injuries
Male
Mice, Inbred C57BL
Myristoylated Alanine-Rich C Kinase Substrate deficiency
NLR Family, Pyrin Domain-Containing 3 Protein metabolism
Non-alcoholic Fatty Liver Disease pathology
Phosphatidylinositol 3-Kinases metabolism
Protective Agents pharmacology
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction drug effects
Abietanes therapeutic use
Myristoylated Alanine-Rich C Kinase Substrate metabolism
Non-alcoholic Fatty Liver Disease drug therapy
Non-alcoholic Fatty Liver Disease metabolism
Protective Agents therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1791-244X
- Volume :
- 42
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- International journal of molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 29620148
- Full Text :
- https://doi.org/10.3892/ijmm.2018.3593