Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis

Abstract

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.

Weighted Gene Co‐Expression Network Analysis Identifies Gender Specific Modules and Hub Genes Related to Metabolism and Inflammation in Response to an Acute Lipid Challenge

“…Cholesterol is an important precursor metabolite with roles in energy metabolism through induction of oxidative stress and other metabolic alterations . Several mitochondrial transport processes can be affected by alterations in cholesterol synthesis . STARD3 is a cholesterol transporter that mediates trafficking of cholesterol to the endoplasmic reticulum, mitochondrial, and plasma membrane .…”

Brazilian propolis mitigates impaired glucose and lipid metabolism in experimental periodontitis in mice

“…P. gingivalis administration also seemed to affect glucose metabolism by increasing the expression of G6pc. G6pc positively regulates gluconeogenesis and can increase blood glucose levels [30]. …”

The role of endosomal cholesterol trafficking protein, StAR-related lipid transfer domain 3 (StarD3/MLN64), in BRIN-BD11 insulinoma cells

“…The START domain of 54kDa endosomal StarD3 (MLN64) is an helix grip fold, providing a hydrophobic binding site for one molecule of cholesterol, facilitating cholesterol trafficking to the endoplasmic reticulum (ER), mitochondria and plasma membrane (Charman et al, 2010; Alpy et al, 2013; van der Kant et al, 2013). Our previous work demonstrated regulation of StarD3 expression by lipid-responsive transcription factors and macrophage sterol content (Borthwick et al 2009) and repression by genetic obesity in hepatic tissues (Soffientini et al, 2014), while overexpression of STARD3 in macrophages enhanced expression of ABCA1 and cholesterol efflux to apoA-I (Borthwick et al, 2010). …”

“…This was a surprising outcome, as expression of STARD3 was clearly sterol-dependent in human THP-1 macrophages (Borthwick et al, 2009) and repressed by genetic obesity in both male and female fa/fa rats (Soffientini et al, 2014). The promoter regions of both rat and human StarD3/STARD3 contain putative binding sites for lipid responsive transcription factors, such as peroxisome proliferator activated receptors, retinoid X receptors and SREBPs (Borthwick et al, 2009), while the marked increases in cholesterol biosynthesis observed in response to cholesterol depletion (Table 1) suggest that SREBP-dependent induction of HMG CoA reductase is operating correctly.…”

“…The former outcome is consistent with the lack of sterol regulation of StarD3 in these cells, but contrasts markedly with findings in other studies. Overexpression of STARD3 increased ABCA1 protein levels, and cholesterol efflux in human THP-1 macrophages (Borthwick et al, 2010) and increased lipidation of exogenous apoA-I in McRH-7777 hepatoma cells (Soffientini et al, 2014). Indeed, StarD3 can access cholesterol in ‘early’ late endosomes and facilitate recycling of this sterol to the plasma membrane, aid the formation of inter-organelle membrane contact sites between late endosomes and the ER, and deliver cholesterol to mitochondria (van der Kant et al, 2013; Alpy et al, 2013); StarD3 is also thought to be involved in actin-mediated dynamics of late endocytic organelles (Holtta-Vuori et al, 2005).…”