Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Plasmalogen modulation is a potential therapy for non-alcoholic fatty liver disease (#77)

Sudip Paul 1 2 3 , Thy Duong 1 , Graeme Lancaster 3 4 , Peter Meikle 1 3 5
  1. Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
  2. Baker Department of Cardiometabolic Heath, University of Melbourne, Melbourne, VIC 3010, Australia
  3. Central Clinical School, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne, VIC 3004, Australia
  4. Haematopoiesis and Leukocyte Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
  5. Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, VIC 3086, Australia

Background:

Plasmalogens are a structurally unique sub-class of glycerophospholipids that possess important biological functions and their level found to be reduced in multiple metabolic disease conditions.  Endogenous plasmalogen levels can be modulated either by targeting the key plasmalogen catabolizing enzyme, lysoplasmalogenase (TMEM86B) or by dietary supplementation of plasmalogen precursors such as alkylglycerols. Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease with increasing prevalence but no current approved treatment. Here, we tested the potential of both genetic and dietary plasmalogen modulation approaches in protecting against NAFLD.

Method:

We generated hepatocyte-specific Tmem86b knockout (Tmem86bLiverKO; Tmem86bflox/floxAlb-Cre) and respective control (Tmem86bflox/flox) mice and exposed them to chow or high-fat diet (40%kcal fat, 2% cholesterol and 20% fructose; HFHCF) for 4, 12 and 24 weeks. Likewise, we exposed wild-type mice to chow or HFHCF diet +/- 1.5% alkylglycerol for 4, 12 and 24 weeks. Metabolic, biochemical, histopathological, and liquid-chromatography mass-spectrometry based lipidomic analyses were performed.

Results:

Tmem86bLiverKO mice had higher hepatic and plasma lysoplasmalogens and plasmalogens compared with control mice. Importantly, fat mass gain was significantly lower in Tmem86bLiverKO mice relative to control mice in response to a HFHCF diet. Tmem86bLiverKO mice also had significantly lower levels of liver function markers in plasma as well as significantly lower liver weights, less hepatic injury and lower hepatic glycerolipid content compared with control mice following HFHCF diet exposure for 4, 12 and 24 weeks. Importantly, the effects of hepatocyte-specific Tmem86b deletion were largely reproduced by alkylglycerol supplementation.

Conclusion:

Our data demonstrate that deletion of Tmem86b increases hepatic plasmalogen levels, and successively provides protection against exacerbated fat mass gain and liver pathologies associated with HFHCF diet feeding in mice, an effect that can be recapitulated by alkylglycerol supplementation. The findings suggest that plasmalogen modulation can be an effective therapeutic strategy for the prevention and management of NAFLD.