Role of FADS1 in Nonalcoholic Fatty Liver Disease (NAFLD)

Shaminie J Athinarayanan, Purdue University

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a rapidly advancing liver disease with very limited treatment options available. One of the main hallmark of NAFLD is lipid profile deregulation, where lack of LCPUFA such as DHA, EPA and AA are often reported in the NAFLD liver samples. The fatty acid desaturase 1 (FADS1), also known as delta-5 desaturase (D5D), is one of the rate-limiting enzymes involved in the desaturation and elongation cascade of PUFA to generate long chain LCPUFA. FADS polymorphisms are often linked to reduced LC-PUFA levels as well as decreased delta-5 enzyme activity in serum and erythrocyte profiles. Our study investigated the association of six GWAS-identified FADS cluster polymorphisms with liver lipid profiles. This study revealed the association between FADS polymorphisms with decreased FADS1 expression and increased hepatic fat content. Those individuals with minor alleles had higher lipid content and reduced FADS1 expression. We also showed that the FADS polymorphisms also altered the liver lipid profiles pattern, where those with minor alleles were associated with increased ratios of saturated to unsaturated phospholipids. We further investigated the molecular mechanism on how FADS1 deregulation facilitate lipid accumulation using both in-vitro and in-vivo models. Downregulating FADS1 increases the susceptibility of hepatocytes to lipid accumulation where else overexpressing FADS1 plays a protective role against lipid accumulation in hepatocytes. Triglyceride and lipid droplets levels were significantly higher in FADS1 null mice when compared to the wild type mice. We showed that fatty acid oxidation, lipogenesis and triglyceride synthesis and storage pathways were altered in the FADS1 deficient condition. Both PPARα and FGF21 mRNA and protein expressions were significantly decreased in the FADS1 knockdown cells and FADS1 null mice. Furthermore, the FGF21 promoter binding activity was significantly reduced in the FADS1 knockdown cells, suggesting a reduced transcriptional activation of the FGF21 gene. Overexpressing FADS1 and treating FADS1 knockdown cells with DHA reduced triglycerides level. DHA treatment also significantly alleviated fatty acid oxidation and lipogenesis pathways. Likewise, DHA treatment also affected the PPARα-FGF21 axis by elevating the expressions of PPARα and FGF21 as well as increasing the FGF21 promoter binding activity. Collectively, these results suggest that deregulation in FADS1 alters the lipid composition in the liver by reducing the amount of important LCPUFAs and altering the PPARα-FGF21 axis.

Degree

Ph.D.

Advisors

Liu, Purdue University.

Subject Area

Genetics|Molecular biology

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