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

CHARACTERISING TTC39C AS A NOVEL REGULATOR OF HEPATIC LIPID METABOLISM (#82)

Aaron Jurrjens 1 2 , Michael F Keating 1 3 , Christine Yang 1 , Simon T Bond 1 3 , Yingying Liu 1 , Kevin H Liu 1 , Yi Wang 1 3 , Kevin Huynh 1 3 4 , Natalie A Mellett 1 , Peter J Meikle 1 2 3 4 , Brian G Drew 1 2 3 , Anna C Calkin 1 2 3
  1. Baker Heart and Diabetes Institute, Melbourne, Australia
  2. Faculty of Medicine, Central Clinical School, Monash University, Melbourne, Australia
  3. Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, Australia
  4. Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, Australia

Non-alcoholic fatty liver disease (NAFLD) affects one third of the Australian population and has a large genetic basis. Despite extensive efforts, findings from human genome-wide association studies (GWAS) explain only a small proportion of the estimated 30% heritability of NAFLD. An alternate approach to human GWAS is to exploit the inherent genetic diversity of a panel of inbred mice. We previously integrated genetic data with liver proteomic and liver and plasma lipidomic data from 107 genetically diverse strains of mice from the Hybrid Mouse Diversity Panel (HMDP). Utilising a range of bioinformatic approaches, we identified numerous known as well as novel targets that regulate hepatic lipid metabolism. The abundance of one target, tetratricopeptide repeat domain 39C (TTC39C), was negatively associated with the abundance of hepatic total cholesteryl esters (CE) as well as numerous triacylglycerol (TAG) species across HMDP strains. We subsequently generated and characterised male and female liver-specific Ttc39c knockout mice (Ttc39cLKO), fed a standard chow diet or high fat, high cholesterol (western) diet for 16 weeks (n=12/group). In male mice fed a chow, but not western diet, Ttc39cLKO was associated with a marked increase in hepatic TAG and CE abundance. Moreover, there was an enrichment in hepatic short-chain TAG species. Consistent with these findings, we observed an elevation in hepatic mRNA and protein expression of markers of de novo lipogenesis, as well as the low-density lipoprotein receptor. Conversely, despite observing no overt influence of genotype on the hepatic or plasma lipidome in female mice fed either diet, female Ttc39cLKO mice exhibited impaired glucose tolerance when fed a chow diet. Collectively, these findings implicate Ttc39c as a novel regulator of lipid and glucose metabolism, in a sex- and diet-dependent manner.