The Zucker fatty rat develops marked hyperlipidemia characterized by elevations in all lipoproteins. The compositions of these lipoproteins are altered. The purpose of our study was to determine the hepatic contribution to the alterations seen in plasma.

Zucker fatty rats and lean controls were fed ad libitum. Fatties gained more weight than leans. Levels of lipids were determined chemically, and apoproteins A(ApoA)-I and B(ApoB) by radioimmunoassay (RIA). Very low density lipoproteins (VLDL) (d < 1.006) and VLDL density subfractions were isolated by ultracentrifugation. VLDL size and density distributions were assessed by column chromatography and ultracentrifugation, respectively. Compositions were studied by isoelectric focusing (IEF) and polyacrylamide gel electrophoresis. Livers from fatty and lean controls were perfused in vitro and whole perfusates and perfusate VLDL were studied as for plasma.

Triglyceride (TG) increased ∼10-fold in fatty plasma, cholesterol (Choi) twofold, and ApoA-I fourfold, but ApoB was ∼40% lower. The VLDL of fatties were larger, TG-enriched, and less dense. Although total VLDL-protein was elevated, the proportion of the VLDL-protein that was ApoB and ARP was low. Therefore, VLDL-protein was enriched with ApoC. ApoB and ApoE contents of VLDL subclasses varied directly with particle density, while ApoC varied inversely. Changes in ApoC subspecies were also noted. For any given VLDL subfraction, fatty VLDL had less ApoB and ApoE and more ApoC than the corresponding VLDL subfraction in the lean controls.

Compared with livers of lean, the livers of fatty rats secreted VLDL that were larger, TG-enriched, and less dense. Here, too, VLDL-protein was higher because of relative increases in non-ApoB proteins. ApoB and ApoE content varied directly with particle density in VLDL subfraction of the perfusates, while ApoC varied inversely; for any given VLDL subfraction, fatty VLDL had less ApoE and more ApoC than analogous fractions in lean controls, though levels of ApoB were similar. As in plasma, the distribution of the ApoC subspecies differed in the perfusate VLDL of fatty and lean animals. Thus, the hepatic secretion of altered VLDL could explain many of the changes seen in the VLDL of plasma. However, differences remained between perfusate and plasma VLDL, which may be due to alterations introduced by intravascular catabolism and/or by lipoproteins secreted from the gut.

Although plasma ApoA-I levels were fourfold higher in fatty, the hepatic secretion of ApoA-I was similar in the fatty and lean rats. The contribution of the liver to plasma pools of A-I was calculated as 34.8% in lean and 10.7% in fatty. These data are consistent with the concept that the gut, not the liver, is the major contributor to plasma ApoA-I.

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