Hepatocyte-specific, PPARγ-regulated mechanisms to promote steatosis in adult mice.

摘要: Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans rodent models, related to a reduction hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are contrast reports suggesting hepatocyte-specific activation PPARγ promotes DNL, triacylglycerol (TAG) uptake acid (FA) esterification. As these could counterbalance positive therapeutic actions delivery TZDs, current study used mouse model adult-onset, (hepatocyte)-specific knockdown (aLivPPARγkd). This has advantages over existing congenital knockout by avoiding compensatory changes embryonic knockdown, thus better modeling impact altering on adult physiology, where metabolic diseases most frequently develop. aLivPPARγkd gene expression endpoints lipid metabolism was examined after 1 or 18 weeks (Chow-fed) 14 low- high-fat (HF) diet. reduced TAG content but did not DNL uptake. However, FA translocase (Cd36), 18-week Chow- HF-fed mice, associated with increased NEFA HF feeding. Also, dramatically Mogat1 expression, reflected an increase monoacylglycerol (MAG) levels, indicative MOGAT activity. These results, coupled previous reports, suggest Cd36-mediated MAG pathway-mediated esterification major targets hepatocyte PPARγ, loss this control explains part protection against steatosis observed aLivPPARγkd.