The bridging function of hepatic lipase reduces both apo-B48- and apo-B100-containing lipoproteins in LDL receptor-deficient "apo-B48-only" and "apo-B100-only" mice

doi:10.1194/jlr.M300459-JLR200

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The bridging function of hepatic lipase reduces both apo-B48- and apo-B100-containing lipoproteins in LDL receptor-deficient "apo-B48-only" and "apo-B100-only" mice

Helén L. Dichek, Kun Qian, and Nalini Agrawal

Pediatrics, University of Washington, Seattle, WA 98195

Corresponding Author: hdichek{at}u.washington.edu

Recent studies indicate that hepatic lipase clears plasma cholesterol by lipolytic and non-lipolytic processing of lipoproteins. We hypothesized that the non-lipolytic processing (known as the bridging function) clears cholesterol by removing apo-B48- and apo-B100-containing lipoproteins, and that this is accomplished by whole particle uptake. To test our hypotheses, we transgenically expressed catalytically inactive human HL (ciHL) in "apo-B48-only" and "apo-B100-only" mice on a background of LDL receptor deficiency. As expected, these mouse models demonstrate that ciHL reduces cholesterol by reducing both apo-B48- and apo-B100-containing lipoproteins. Specifically, expression of ciHL in LDLR-deficient "apo-B48-only" mice reduced cholesterol mainly by reducing LDL-C (by 54%, from 46 ± 6 to 19 ± 8 mg/dl, P< 0.001). Apo-B48 was similarly reduced (by ~ 60 %). The similar reductions in LDL-C and apo-B48 indicate cholesterol removal by whole particle uptake in the "apo-B48-only" background. Expression of ciHL in LDLR-deficient "apo-B100-only" mice reduced cholesterol mainly by reducing IDL-C (by 37 %, from 61 ± 19 to 38 ± 12 mg/dl, P< 0.003). Apo-B100 was also reduced (by 27%). Next, the contribution of nutritional influences to the bridging function was examined with a high-fat diet challenge in the "apo-B100-only" background. As seen on the chow diet, expression of ciHL on the high fat diet also reduced IDL-C (by ~30%, from 355 ± 72 to 257 ± 64 mg/dl, P< 0.04). However, the apo-B100 remained unchanged. The reduction of IDL-C in excess of apo-B100 suggests removal either by selective cholesterol ester uptake, or by selective removal of larger, cholesterol ester enriched particles, thereby leaving smaller cholesterol ester poor particles in plasma. Our results demonstrate that the bridging function facilitates removal of apo-B48- and apo-B100-containing lipoproteins by whole particle uptake and other mechanisms.

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