Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Abstract

Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), an endothelial cell protein, binds LPL in the subendothelial spaces and transports it to the capillary lumen. In Gpihbp1−/− mice, LPL remains stranded in the subendothelial spaces, causing hypertriglyceridemia, but how Gpihbp1−/− mice respond to metabolic stress (e.g., cold exposure) has never been studied. In wild-type mice, cold exposure increases LPL-mediated processing of triglyceride-rich lipoproteins (TRLs) in brown adipose tissue (BAT), providing fuel for thermogenesis and leading to lower plasma triglyceride levels. We suspected that defective TRL processing in Gpihbp1−/− mice might impair thermogenesis and blunt the fall in plasma triglyceride levels. Indeed, Gpihbp1−/− mice exhibited cold intolerance, but the effects on plasma triglyceride levels were paradoxical. Rather than falling, the plasma triglyceride levels increased sharply (from ∼4,000 to ∼15,000 mg/dl), likely because fatty acid release by peripheral tissues drives hepatic production of TRLs that cannot be processed. We predicted that the sharp increase in plasma triglyceride levels would not occur in Gpihbp1−/−Angptl4−/− mice, where LPL activity is higher and baseline plasma triglyceride levels are lower. Indeed, the plasma triglyceride levels in Gpihbp1−/−Angptl4−/− mice fell during cold exposure. Metabolic studies revealed increased levels of TRL processing in the BAT of Gpihbp1−/−Angptl4−/− mice.

Novel GPIHBP1-independent pathway for clearance of plasma TGs in Angptl4−/−Gpihbp1−/− mice

“…However, the whole lipoprotein uptake in Angptl4 / Gpihbp1 / mice was not any greater than that observed in Gpihbp1 / mice. This result is consistent with the recent report from Larsson et al (32), who also found that at room temperature, TG uptake, but not lipoprotein particle uptake (as measured by uptake of radiolabeled retinol), was increased in the BAT of Angptl4 / Gpihbp1 / mice compared with Gpihbp1 / mice. Although there was no increase in whole lipoprotein uptake, the already substantial uptake in Angptl4 / Gpihbp1 / mice may explain the improved TG Fig.…”

“…Indeed, Dijk et al (31) proposed that an alternative ANGPTL4-sensitive pathway might allow transport of LPL in the absence of GPIHBP1 and ANGPTL4. In support of this idea, using immunofluorescence, a study by Larsson et al (32) found some evidence of LPL on the vascular lumen of capillaries in Angptl4 / Gpihbp1 / mice. In contrast, we found no evidence of increased LPL entry into the vasculature.…”

“…The uptake of whole TG-rich lipoprotein particles into BAT has been described previously (24)(25)(26), but in normal mice the contribution of whole lipoprotein uptake to brown adipose fatty acid uptake appears to be far less than that from classical LPL lipolysis (24). Importantly, reduction of ANGPTL4 is important for the increase in whole lipoprotein uptake into BAT that occurs with cold exposure (26), and deletion of ANGPTL4 in Gpihbp1 / mice increases cold-induced whole lipoprotein uptake compared with deletion of GPIHBP1 alone (32). Our model implies not only that whole lipoprotein particles pass through the capillary wall and enter the interstitial space, but also that these lipoprotein particles also can return to the circulation, a concept that has not yet been tested.…”

Regulation of angiopoietin-like protein 8 expression under different nutritional and metabolic status

“…These processes ensure the energy supply to maintain the physiological functions of the body. On the contrary, fasting caused up-regulation of ANGPTL4 in WAT [21,39]. The up-regulated ANGPTL4 reduces the uptake of circulating triglycerides by WAT through reducing LPL activity.…”

“…Under starvation, the expression of ANGPTL8 decreased by nearly 70% in WAT [21], and the expression of ANGPTL8 in BAT and liver was also significantly reduced [39]. Under starvation, circulating ANGPTL8/ANGPTL3 complex reduces [10], which increases LPL activity in peripheral tissues and in turns increases the uptake of VLDL by skeletal muscles and the heart.…”