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

Seungtae On,Hyun Young Kim,Keon Wook Kang,Hyo Seon Kim,Jeongwoo Park

doi:10.3390/ijms20112625

Seungtae On, Hyun Young Kim + Show 3 more

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https://doi.org/10.3390/ijms20112625

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Abstract

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 confirmed that DHA treatment reduced the number of larger ( >10 μm2) LDs, as well as the total area of LDs. Moreover, DHA lowered protein and mRNA expression levels of lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase and stearoyl-CoA desaturase-1 (SCD-1) in primary hepatocytes incubated with liver X receptor (LXR) agonist T0901317 or high glucose and insulin. DHA also decreased protein expression of nuclear and precursor sterol response-element binding protein (SREBP)-1, a key lipogenesis transcription factor. We further found that exposure of murine primary hepatocytes to DHA for 12 h increased GPR40 and GPR120 mRNA levels. Specific agonists (Compound A for GPR120 and AMG-1638 for GPR40), hepatocytes from GPR120 knock-out mice and GPR40 selective antagonist (GW1100) were used to assess whether DHA’s antilipogenic effects are mediated through GPR120 or GPR40. Compound A did not decrease SREBP-1 and FAS protein expression in hepatocytes exposed to T0901317 or high glucose with insulin. Moreover, DHA downregulated lipogenesis enzyme expression in GPR120-null hepatocytes. In contrast, AMG-1638 lowered SREBP-1 and SCD-1 protein levels. Additionally, GW1100, a GPR40 antagonist, reversed the antilipogenic effects of DHA. Collectively, our data demonstrate that DHA downregulates the expression SREBP-1-mediated lipogenic enzymes via GPR40 in primary hepatocytes.

Highlights

Nonalcoholic fatty liver disease (NAFLD) affects 80–100 million people in the U.S alone [1]
The levels of fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1) were diminished in mouse primary hepatocytes treated with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) for 12 h, and the degree of inhibition was more prominent in DHA-treated hepatocytes (Figure 1A)
The levels of preSREBP-1, FAS, and ACC were marginally elevated by T090, all the protein expression decreased in response to the DHA treatment (Figure 1D and Figure S2A)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) affects 80–100 million people in the U.S alone [1]. Most patients in the U.S, who visit primary care providers for routine checkup have elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which are markers of liver damage [2]. Among those with elevated AST and ALT levels, 33 percent are eventually diagnosed with NAFLD [2]. In Asia, 25 percent of individuals aged >18 years are diagnosed with NAFLD [3] Even though this widespread disease has no specific signs or symptoms, it can progress to nonalcoholic steatohepatitis (NASH) and eventually lead to cirrhosis [4]. Treatment options for NAFLD are limited, thiazolidinediones and vitamin E have been proven to effectively manage symptoms [5]

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