Involvement of G-Protein-Coupled Receptor 40 in the Inhibitory Effects of Docosahexaenoic Acid on SREBP1-Mediated Lipogenic Enzyme Expression in Primary Hepatocytes

  title={Involvement of G-Protein-Coupled Receptor 40 in the Inhibitory Effects of Docosahexaenoic Acid on SREBP1-Mediated Lipogenic Enzyme Expression in Primary Hepatocytes},
  author={Seungtae On and Hyun Young Kim and Hyo Seon Kim and Jeong Hill Park and Keon Wook Kang},
  journal={International Journal of Molecular Sciences},
Nonalcoholic fatty liver disease is a frequent liver malady, which can progress to cirrhosis, the end-stage liver disease if proper treatment is not applied. Omega-3 fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid, have been clinically proven to lower serum triglyceride levels. Various physiological activities of omega-3 fatty acids are due to their agonistic actions on G-protein-coupled receptor 40 (GPR40) and GPR120. Lipid droplets (LD) accumulation in hepatocytes… 
High omega arachidonic acid/docosahexaenoic acid ratio induces mitochondrial dysfunction and altered lipid metabolism in human hepatoma cells
High AA:DHA ratio induced triglyceride accumulation, increased oxidative stress and disrupted mitochondrial functions, and Stimulation of lipogenic and steroidal transcription factors may partly mediate these effects and contribute to NAFLD development.
G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment
The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids, and understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.
Synthesis of DHA (omega-3 fatty acid): FADS2 gene polymorphisms and regulation by PPARα
If DHA simultaneously binds to both phosphorylated PPARα and RXRα, the resulting DHA-PPARαP-RXRα-DHA heterodimer represses FADS2 gene via PPRE, which results in a decreased production of D6D and DHA.
Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View
It is concluded that future studies in NAFLD patients using combined supplementations such as DHA plus HT are warranted to prevent liver steatosis, thus avoiding its progression into more unmanageable stages of the disease.
Free Fatty Acid Receptors as Mediators and Therapeutic Targets in Liver Disease
In this review, an in-depth, focused summary of the role FFARs play in liver health and disease is provided.
Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD
The functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes are described and could lead to the development of novel drugs that are clinically useful for the treatment of various metabolic diseases.
A high fat diet with a high C18:0/C16:0 ratio induced worse metabolic and transcriptomic profiles in C57BL/6 mice
The high fat diet with a high C18:0/C16:0 ratio induced more severe glucose and lipid metabolic disorders and inflammation and affected expression of more lncRNAs and mRNAs than an isocaloric low C18?:0/ C16: 0 ratio diet in mice.


Omega-3 polyunsaturated fatty acids protect human hepatoma cells from developing steatosis through FFA4 (GPR120).
LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1 Published, JLR Papers in Press, February 16, 2004. DOI 10.1194/jlr.M400011-JLR200
It is suggested that LXR/RXR ligands generate ABCA1-destabilizing monounsaturated fatty acids from their saturated precursors by activating SCD, and with cholesterol-loaded macrophages exposed to saturated fatty acids, activated LXR or RXR may counteract the enhancedABCA1 transcription by reducing the ABCA 1 protein content.
Biochemical and physiological function of stearoyl-CoA desaturase.
  • C. Paton, J. Ntambi
  • Biology
    American journal of physiology. Endocrinology and metabolism
  • 2009
Oleate is the most abundant monounsaturated fatty acid in dietary fat and is therefore readily available, and inhibition of its expression could be of benefit for the treatment of obesity, diabetes, and other metabolic diseases.
GPR40 agonist ameliorates liver X receptor-induced lipid accumulation in liver by activating AMPK pathway
It is demonstrated that GW9508 exerts a beneficial effect to ameliorate LXR-induced hepatic steatosis through regulation of AMPK signaling pathway.
The Orphan G Protein-coupled Receptor GPR40 Is Activated by Medium and Long Chain Fatty Acids*
expression analysis by quantitative reverse transcription-PCR showed that GPR40 was specifically expressed in brain and Pancreas, with expression in rodent pancreas being localized to insulin-producing β-cells.
The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia
Proposed mechanisms of action of OM3FAs include inhibition of diacylglycerol acyltransferase, increased plasma lipoprotein lipase activity, decreased hepatic lipogenesis, and increased hepatic β-oxidation, which are thought to provide a better indication of cardiovascular risk in this patient population.
The Pharmacology of TUG-891, a Potent and Selective Agonist of the Free Fatty Acid Receptor 4 (FFA4/GPR120), Demonstrates Both Potential Opportunity and Possible Challenges to Therapeutic Agonism
TUG-891 [3-(4-((4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4
A Gpr120 Selective Agonist Improves Insulin Resistance and Chronic Inflammation
It is reported that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo, suggesting that GPR120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.