title: Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis.
abstract: OBJECTIVE
  To examine hepatic expression of cholesterol-trafficking proteins, mitochondrial StarD1 and endosomal StarD3, and their relationship with dyslipidaemia and steatosis in Zucker (fa/fa) genetically obese rats, and to explore their functional role in lipid metabolism in rat McArdle RH-7777 hepatoma cells.
  
  
  METHODS
  Expression of StarD1 and StarD3 in rat liver and hepatoma samples were determined by Q-PCR and/or immunoblotting; lipid mass by colorimetric assays; radiolabelled precursors were utilised to measure lipid synthesis and secretion, and lipidation of exogenous apolipoprotein A-I.
  
  
  RESULTS
  Hepatic expression of StarD3 protein was repressed by genetic obesity in (fa/fa) Zucker rats, compared with lean (Fa/?) controls, suggesting a link with storage or export of lipids from the liver. Overexpression of StarD1 and StarD3, and knockdown of StarD3, in rat hepatoma cells, revealed differential effects on lipid metabolism. Overexpression of StarD1 increased utilisation of exogenous (preformed) fatty acids for triacylglycerol synthesis and secretion, but impacted minimally on cholesterol homeostasis. By contrast, overexpression of StarD3 increased lipidation of exogenous apoA-I, and facilitated de novo biosynthetic pathways for neutral lipids, potentiating triacylglycerol accumulation but possibly offering protection against lipotoxicity. Finally, StarD3 overexpression altered expression of genes which impact variously on hepatic insulin resistance, inducing Ppargcla, Cyp2e1, Nr1h4, G6pc and Irs1, and repressing expression of Scl2a1, Igfbp1, Casp3 and Serpine 1.
  
  
  CONCLUSIONS
  Targeting StarD3 may increase circulating levels of HDL and protect the liver against lipotoxicity; loss of hepatic expression of this protein, induced by genetic obesity, may contribute to the pathogenesis of dyslipidaemia and steatosis.
authors.affiliation: Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.
authors.forename: Ugo
authors.initials: U
authors.lastname: Soffientini
authors.affiliation: Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Caridis
authors.affiliation: Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK.
authors.forename: Sharron
authors.initials: S
authors.lastname: Dolan
authors.affiliation: Diabetes Research Group, Institute for Applied Health Research and the Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK. Electronic address: Ann.Graham@gcu.ac.uk.
authors.forename: Annette
authors.initials: A
authors.lastname: Graham
keywords: Cholesterol trafficking proteins; Dyslipidaemia; High density lipoprotein; Insulin resistance; Lipid metabolism; Steatosis