Studies on the mechanism of hypertriglyceridemia in the genetically obese Zucker rat

The possibility that impaired removal of lipoprotein triglyceride from the circulation may be a participating factor in the hypertriglyceridemia of the obese Zucker rat was examined. We found no significant differences in the heparin-released lipoprotein lipase (LPL) activities of the adipose tissue, skeletal muscle, and heart (expressed per gram of tissue) from the lean and obese Zucker rats. Furthermore, the kinetic properties of adipose tissue and heart LPL from the lean and obese rats were similar, indicating that the catalytic efficiency of the enzyme was unaltered in the obese animals. The postheparin plasma LPL activities of lean and obese rats were also similar. However, the postheparin plasma hepatic triglyceride lipase (H-TGL) activity in the obese rats was elevated. The higher activity of H-TGL could not alleviate the hypertriglyceridemia in these animals. Since hypertriglyceridemia in the obese rats could also be due to the hepatic production of triglyceride-rich lipoproteins which are resistant to lipolysis, we therefore isolated very low density lipoproteins (VLDL) from lean and obese rat liver perfusates and examined their degradation by highly purified human milk LPL. Although certain differences were observed in hepatic VLDL triglyceride fatty acid composition, the kinetic patterns of LPL-catalyzed triglyceride disappearance from lean and obese rat liver perfusate VLDL were similar. The isolated liver perfusate VLDL contained sufficient apolipoprotein C-II for maximum lipolysis. These results indicate that impaired lipolysis is not a contributing factor in the genesis of hypertriglyceridemia in the genetically obese Zucker rat. The hyperlipemic state may be attributed to hypersecretion of hepatic VLDL and consequent saturation of the lipolytic removal of triglyceride-rich lipoproteins from the circulation.     

Nonreceptor-mediated responses of adenylate cyclase in membranes from liver, muscle, and white and brown adipose tissue of obese (fa/fa) and lean (Fa/) Zucker rats

Adenylate cyclase activity was determined in membranes of liver, muscle, white adipose tissue, and brown adipose tissue (BAT) of lean (Fa/) and obese (fa/fa) Zucker rats. Responses were monitored following beta-adrenergic receptor stimulation and addition of GTP, GTP gamma S, or forskolin. beta-Adrenergic responses in liver, white adipose tissue, and BAT were lower in obese than in lean animals. No such difference was observed in muscle membranes. Production of cAMP after addition of guanine nucleotides was lower in liver and white adipose tissue membranes from obese rats compared with their lean littermates. Synthesis of cAMP in muscle membranes of obese animals after addition of GTP was either not different, or slightly higher, than that observed in muscle membranes from lean animals. Furthermore, production of cAMP after forskolin addition to muscle membranes of obese rats was significantly higher than that observed from lean rats under the same conditions. Interestingly, BAT membranes of obese rats were significantly more sensitive to guanine nucleotide activation than those of lean animals. The results confirm recent findings indicating inferior function of G proteins in liver plasma membranes of obese Zucker rats, and extend this observation to adipose tissue. The present results further suggest that the "nonreceptor" components (e.g., G proteins) responsible for the activation of adenylate cyclase in BAT membranes of obese rats are more responsive to stimulation than those of lean animals. Such sensitivity may be related to and perhaps compensate for the reduced thermogenic activity in the obese Zucker rat during the development of obesity.     

Contributions of fatty acid and sterol synthesis to triglyceride and cholesterol secretion by the perfused rat liver in genetic hyperlipemia and obesity

The relative importance of fatty acid synthesis in triglyceride secretion by perfused livers from lean (normal control) and obese Zucker rats was investigated. Livers from fed animals were perfused in a recirculating system with tritiated water and a constant infusion of oleic acid. Triglyceride secretion was 5 times greater and cholesterol secretion was 35% greater in the obese rat livers. The very-low-density lipoprotein hypersecreted by perfused livers from obese rats contained more apolipoprotein B and exhibited an increased B-48/B-100 ratio. Apo-B was also elevated in the hypertriglyceridemic plasma of obese rats in both fed and fasting states. The very-low-density lipoprotein isolated therefrom was likewise characterized by an increased B-48/B-100 ratio. Ketogenesis was depressed 40% in the obese rat livers and increased hepatic malonyl-CoA was implicated in this alteration. The de novo synthesis and secretion of newly synthesized cholesterol was moderately increased in the perfused livers from obese rats. Tritium incorporation into fatty acids was 15 times greater in the obese genotype. Most of the synthesized fatty acids remained in the liver and were recovered after perfusion in triglyceride and phospholipids. Newly synthesized fatty acids accounted for only 3 and 15% of the triglyceride secreted by the lean and obese rat livers, respectively. A large portion of the secreted triglyceride fatty acids was derived from endogenous liver lipids. When the turnover of newly synthesized fatty acids in these pools was considered, the contribution of de novo fatty acid synthesis to triglyceride secretion was estimated to be 9% in the lean and 44% in the obese rat livers. Therefore, the altered partition of free fatty acids (Fukuda, N., Azain, M. J., and Ontko, J. A. (1982) J. Biol. Chem. 257, 14066-14072) and increased fatty acid synthesis are both major determinants of the hypersecretion of triglyceride-rich lipoproteins by the liver in the genetically obese Zucker rat.     

Regulatory enzymes of lipid metabolism in LA/N-cp rats

Hepatic activities of rate limiting enzymes in fatty acid and cholesterol synthesis and cholesterol degradation were determined in lean and obese LA/N-cp rats. The hepatic activities of acetyl-CoA carboxylase and fatty acid synthetase, the key enzymes of fatty acid synthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase (the rate limiting enzyme in cholesterol synthesis), were increased 2-fold in the obese rats as compared with their lean littermates. In contrast, the activity of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of cholesterol degradation to bile acids, was significantly decreased by 28% in the obese group as compared with the control group. Significantly, compared with the control group, the obese animals exhibited similar magnitudes of differences in the activities of the above enzymes even when they were pair-fed with the control animals. Thus these differences in the obese group are not due to hyperphagia but possibly to hypersecretion of the lipogenic hormone, insulin in this strain. These results indicate that the LA/N-cp obese rat has twice the capacity to synthesize body fat and cholesterol but has a reduced capacity to degrade the cholesterol, leading to increased accumulation of cholesterol and fat.     

Effects of phenotype, sex, and diet on plasma lipids in LA/N-cp rats

The LA/N-corpulent (cp) rat is a recently developed congenic strain which exhibits obesity. The effects of phenotype and sex on serum and lipoprotein lipid content were examined in LA/N-cp rats fed either a control or an atherogenic diet high in saturated fat and protein. Obese rats were pair-fed to equivalent lean animals. Results from this study indicate that sex, phenotype, and diet exert significant effects on plasma and lipoprotein cholesterol content. Plasma cholesterol levels were higher in obese compared with lean rats, females than in males, and rats consuming the atherogenic diet compared with the control diet. Plasma and lipoprotein triglyceride levels were significantly increased only in obese compared with lean animals. The increased plasma cholesterol and triglyceride was observed primarily in the chylomicron and very low density lipoprotein fractions. Increased levels of plasma cholesterol were not a result of increased dietary cholesterol absorption or increased liver cholesterol biosynthesis. These data suggest that LA/N-cp rats can serve as a unique rodent model for the study of the interrelationships between hyperlipidemia, obesity, and coronary heart disease.     

Fatty acid synthesis in liver and adipose tissue of normal and genetically obese (ob/ob) mice during the 24-hour cycle.

1. The synthesis of long-chain fatty acids de novo was measured in the liver and in regions of adipose tissue in intact normal and genetically obses mice throughout the daily 24h cycle. 2. The total rate of synthesis, as measured by the rate of incorporation of 3H from 3H2O into fatty acid, was highest during the dark period, in liver and adipose tissue of lean or obese mice. 3. The rate of incorporation of 14C from [U-14C]glucose into fatty acid was also followed (in the same mice). The 14C/3H ratios were higher by a factor of 5-20 in parametrial and scapular fat than that in liver. This difference was less marked during the dark period (of maximum fatty acid synthesis). 4. In normal mice, the total rate of fatty acid synthesis in the liver was about twofold greater than that in all adipose tissue regions combined. 5. In obese mice, the rate of fatty acid synthesis was more rapid than in lean mice, in both liver and adipose tissue. Most of the extra lipogenesis occurred in adipose tissue. The extra hepatic fatty acids synthesized in obese mice were located in triglyceride rather than phospholipid. 6. In adipose tissue of normal mice, the rate of fatty acid synthesis was most rapid in the intra-abdominal areas and in brown fat. In obese mice, all regions exhibited rapid rates of fatty acid synthesis. 7. These results shed light on the relative significance of liver and adipose tissue (i.e. the adipose 'organ') in fatty acid synthesis in mice, on the mino importance of glucose in hepatic lipogenesis, and on the alterations in the rate of fatty acid synthesis in genetically obese mice.     

Increased growth hormone binding to liver membranes of obese Zucker rats

Developmental changes in hepatic growth hormone binding sites were examined in the genetically obese male fa/fa rats and in the lean littermates. At 16 days, fa/fa pups are normoinsulinemic; the specific binding of 125I-hGH to liver membranes is comparable in the two genotypes. At 4 weeks and later on, plasma membranes and Golgi fractions of male obese Zucker rats have more GH binding sites than lean littermates. The GH pituitary content is comparable in the two genotypes from 2 to 8 weeks and in 14-week-old fa/fa rats it is half that in lean animals. In the two genotypes plasma IGFI dramatically increases during puberty. At 4 weeks, plasma IGFI level is significantly higher in fa/fa rats than in lean littermates. In this model of genetic obesity, an increased GH binding to liver membranes is observed after the third week of life, shortly after the onset of hyperinsulinemia in the fa/fa rat.     

Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat.

The corpulent JCR:LA-cp rat (cp/cp) is a useful model for study of the metabolic consequences of obesity and hyperinsulinemia. To assess the effect of hyperinsulinemia on VLDL secretion in this model, we measured rates of secretion of VLDL in perfused livers derived from cp/cp rats and their lean littermates. Livers of cp/cp rats secreted significantly greater amounts of VLDL triglyceride and apolipoprotein, compared with lean littermates. The content of apoB, apoE, and apoCs in both perfusate and plasma VLDL was greater in the cp/cp rat, as was the apolipoprotein (apo)C, apoA-I, and apoA-IV content of plasma HDL. Triglyceride content was also greater in cp/cp livers, as was hepatic lipogenesis and expression of lipogenic enzymes and sterol regulatory element binding protein-1 (SREBP-1). Hepatic mRNAs for apoE, and apoA-I were higher in livers of cp/cp rats. In contrast, the steady state levels of apoC-II, apoC-III, and apoB mRNAs were unchanged. Thus, livers of obese hyperinsulinemic cp/cp JCR:LA-cp rats secrete a greater number of VLDL particles that are enriched in triglyceride, apoE, and apoC. Greater secretion of VLDL in the cp/cp rat in part results from higher endogenous fatty acid synthesis, which in turn may occur in response to increased expression of the lipogenic enzyme regulator SREBP-1c.     

Plasma lipoproteins and the synthesis and turnover of plasma triglyceride in normal and genetically obese mice

1. Lipoproteins in the plasma of mice were characterized by agarose-gel chromatography and polyacrylamide-gel electrophoresis: genetically obese (ob/ob) mice exhibited hyperlipoproteinaemia (compared with lean mice), largely owing to an increase in the concentration of cholesterol in high-density lipoprotein. Plasma concentrations of triglyceride and phospholipid were not markedly increased in genetically obese mice. 2. The formation of glycerolipids in liver and plasma was investigated with (14)C-labelled precursors. The synthesis of hepatic triglyceride and phospholipid from glucose or palmitate was enhanced in ob/ob mice, compared with lean mice. The rate of entry of triglyceride into plasma, calculated from the time-course of incorporation of (14)C from [(14)C]palmitate into plasma triglyceride, was increased in ob/ob mice (0.5mumol of fatty acid/min, compared with 0.2 in lean mice). 3. The removal from plasma of murine lipoprotein triglyceride-[(14)C]fatty acid was increased in ob/ob mice (half-time 2.2min, compared with 7.2min in lean mice). Similar results were obtained with an injected lipid emulsion (Intralipid). 4. From these measurements, estimates of the rates of turnover of plasma triglyceride in mice (fed on a mixed diet, female, 3 months old) are about 1.0mumol of fatty acid/min in ob/ob mice, and 0.25 in lean mice. 5. The major precursor of hepatic and plasma triglyceride in lean and ob/ob mice was calculated to be plasma free fatty acid. 6. These results are discussed, in connexion with the role of the liver in triglyceride metabolism in mice, especially in relation to genetic obesity.     

Ketone body utilization for lipogenesis in the perfused liver of the obese Zucker rat

The purpose of these studies was to determine if the utilization of ketone bodies as a carbon source for lipogenesis could account for the decreased ketone body production by livers of obese Zucker rats, as well as contribute to the enhanced rates of fatty acid synthesis observed in these animals. Ketone body production was decreased from 822 mumol/liver in the lean to 538 mumol/liver in the obese genotype (P less than 0.05). The incorporation of ketone bodies into fatty acids was significantly greater in the obese rat liver (lean, 1.95 mumol of ketone bodies/liver, versus obese, 35.22 mumol/liver; P less than 0.025). The relative contribution of this pathway to the overall rate of fatty acid synthesis was not affected by genotype and accounted for only 3 to 4% of the fatty acids synthesized. The incorporation of ketone bodies into digitonin precipitable sterols was similar in the two genotypes (lean, 4.5 mmol/liver, versus obese 4.7 mumol/liver; NS). This accounted for 9.2 and 6.3% of the total sterol synthesis in lean and obese rat livers, respectively. The total incorporation of ketone bodies into lipid was 7.5 mumols in the lean rat livers and 42.0 mumoles in the obese (P less than 0.025). The net increase was 35 mumoles incorporated, whereas the net decrease in ketogenesis was 284 mumoles. Thus, although ketone body carbon utilization for lipid synthesis was increased in the liver of the obese rats, this pathway could only account for a fraction of the genotypic difference in ketone body production and was of relatively minor importance as a source of carbon for hepatic fatty acid synthesis in both lean and obese rats.     

高果糖引起的脂肪肝大鼠肾脏脂质合成相关基因和蛋白的表达

大量研究表明,高果糖可引起脂肪肝,但对肾脏脂质代谢的影响尚不清楚。该实验研究给予10％果糖水5周后诱导的脂肪肝大鼠肾脏的脂质代谢情况,并探讨其可能机制。将16只雄性SD大鼠随机分为正常组（con）和果糖组（fru）,果糖组给予10％（W／V）果糖水,第5N末称体重、取血、处死,检测血浆GLU、TG、TC和INSULIN含量。取肾脏、肝脏和白色脂肪称重,采用形态学方法观察肝脏和肾脏脂质沉积情况,酶法测其TG、TC含量,以Real time—PCR检测肾脏、肝脏中脂质合成和脂质氧化相关基因水平,以Westemblot检测肾、肝细胞核脂质合成转录因子的蛋白表达。结果显示,果糖组大鼠血浆TG、INSULIN明显升高,并出现肥胖体征,肝脏脂质沉积严重,其调控脂质合成的两个关键的转录因子ChREBP和SREBPlcmRNA和核蛋白表达都明显升高,并且它们靶向的脂质合成相关酶FAS、ACCl、SCDlmRNA表达也显著增加。但是,在肾脏中,高果糖没有引起TG含量的变化,调控脂质重新合成的基因和蛋白的表达也未发生变化。因此,与果糖致脂肪肝不同,高果糖饮食并没有造成肾脏的脂质沉积和脂质合成相关基因、蛋白的变化。     

Early development of adipose cell lipogenesis and glycerol utilization in Zucker obese rats.

A study of adipose cell metabolism was made at ages 5, 7, 10, and 14 wk of age in genetically obese Zucker rats. Adipose samples were surgically removed and used for in vitro adipose cell incubations and for characterization of enzyme patterns. Lipogenic capacity from glucose and enzymes normally associated with lipogenesis (malic enzyme, citrate cleavage enzyme and glucose-6-PO4 dehydrogenase) followed the same pattern of development. At 5 wk of age, the adipose cells of obese animals had a greater capacity for fat synthesis than the lean rats. At all other ages lipogenic activity and enzyme levels were either similar or less than the pair-fed lean littermates. Glycerol utilization by isolated fat cells was similar; however, adipose tissue glycerokinase was elevated in obese rats at 14 wk of age. It was concluded that there was no apparent change in specific lipogenic capacity of fat cells from the obese rat when compared to its lean littermate. It was also concluded that increased adipose glycerokinase activity in obese rats represented a secondary shift in metabolism.     

Effects of starvation on the tissular lipogenic rate in the obese Zucker rat.

The lipogenic rate of the obese rats was significantly higher than that of the lean rats in liver, white adipose tissue, skeletal muscle, heart and carcass. In the lean rats, a 24 h starvation period caused a significant decrease in the lipogenic rate of white adipose tissue and skeletal muscle while it increased that of heart, brain and brown adipose tissue. In the obese rats, starvation decreased the lipogenic rate in liver, skeletal muscle, white adipose tissue, brown adipose tissue and carcass. In spite of this, liver and skeletal muscle showed higher rates of lipid synthesis than the corresponding fed lean. It is concluded that starvation induces a qualitatively similar response in the obese versus the lean rat although the total lipogenic capacity of the animal is still higher.     

Dissociation of hepatic cholesterol synthesis from hepatic low-density lipoprotein uptake and biliary cholesterol saturation in female and male hamsters of different ages

These studies were carried out in order to examine the relationship between the rate of uptake of low-density lipoproteins (LDL) by the liver and the rates of hepatic and extrahepatic cholesterol synthesis and biliary cholesterol content. Female hamsters fed a regular chow diet manifested a rate of hepatic sterol synthesis that was several-fold higher than that in age-matched males maintained on the same diet. Synthesis in the small intestine did not show a corresponding sex difference, but the overall rate in the remaining tissues of the carcass was significantly lower in the females than in the males. Thus, although the proportion of newly synthesized sterol produced by the liver was substantially greater in the females, this was balanced by a smaller contribution from the extrahepatic compartment so that whole-body sterol synthesis was similar in the females and males. Sterol synthesis in the whole animal declined markedly with age in both the females and males, and this was due principally to a reduction in extrahepatic synthesis. Despite the higher rate of hepatic synthesis in females, the rate of uptake of [14C]sucrose-labeled, homologous LDL by the liver was similar in females and males. In males, the adrenal gland transported the labeled LDL at a much higher rate than in females, but in the other extrahepatic tissues the rate of LDL uptake was similar in both groups. The level of cholesterol carried in the various plasma lipoprotein fractions and the relative cholesterol content of gallbladder bile were also similar in females and males. Thus, in this experimental model, the rate of LDL transport by the liver and extrahepatic tissues, the amount of cholesterol carried in plasma lipoproteins and the degree of biliary cholesterol saturation were not directly related to the rates of endogenous hepatic and extrahepatic sterol synthesis.     

Lipoprotein lipase and cholesterol transfer activities of lean and obese Zucker rats.

Adult female lean and obese Zucker rats maintained under standard conditions were used for the estimation of plasma, liver and white adipose tissue (WAT) activity of lipoprotein lipase, plasma and liver hepatic lipase and plasma lecithin-cholesterol acyltransferase. No differences in plasma or tissue levels of lipoprotein lipase between lean and obese rats were detected, but the larger WAT size of the obese rats resulted in higher lipase activity per unit of rat weight. Hepatic lipase levels in plasma were higher in the obese, but in liver, the higher activity was found in lean rats. No significant differences were found for lecithin-cholesterol acyltransferase activity, except when the levels in the HDL fraction were expressed per unit of protein weight, showing lower activity in the obese rats. In conclusion, the essentially maintained enzyme activities in obese rat tissues suggest that they cannot explain the deficient lipoproteins processing of obese rats, and, consequently their dislipidaemia.     

Expression of hepatic microsomal cholesterol 7 alpha-hydroxylase activity in lean and obese Zucker rats

The activity of hepatic microsomal cholesterol 7 alpha-hydroxylase was studied in genetically obese and lean Zucker rats. The liver microsomal cholesterol 7 alpha-hydroxylase activity in fatty Zucker rats (fa/fa) is about 50% to 70% lower than that of the lean (Fa/-) rats of the same sex, when animals were sacrificed at the middle of the dark cycle. When rats were sacrificed at the middle of the light cycle, cholesterol 7 alpha-hydroxylase activity was the same as in the dark cycle in obese rats of both sexes, but was 65% lower in lean rats. However, cholesterol 7 alpha-hydroxylase activity was stimulated by the treatment with cholestyramine in both obese and lean rats. Our results suggested that the diurnal regulation of cholesterol 7 alpha-hydroxylase activity is lost in obese rats but was present under cholestyramine treatment in the genetically obese strain of rats.     

Amino acid metabolism in several tissues of the obese Zucker rat as indicated by the tissue accumulation of α-amino[1-14C]isobutyrate

Measurements of the tissue accumulation of α-amino[1-¹⁴C]isobutyrate [1-¹⁴C]AIB) in lean (+/?) and obese (fa/fa) Zucker rats showed an augmented tissue/plasma ratio in the liver of the obese animals. In contrast, brown adipose tissue AIB accumulation was lower in the fa/fa animals. In response to a 24h starvation period AIB accumulation was significantly elevated in the liver and plasma of the lean animals and was unchanged in the liver of the fa/fa animals. The circulating concentration of alanine and branched-chain amino acids was elevated in the fa/fa animals as compared to their lean counterparts. These observations suggest that amino acid uptake is not involved in the impaired muscle development observed in the obese Zucker rat and that the ability of brown adipose tissue for amino acid utilization is decreased in the obese animals suggesting that this may partially explain the impaired thermoregulatory capacity observed in brown adipose tissue of obese Zucker rats.     

Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice

Excess hepatic lipid accumulation and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD). Thus, we hypothesized that the hypolipidemic and antioxidant activities of green tea extract (GTE) would attenuate events leading to NAFLD. Obese mice (ob/ob; 5 weeks old, n=38) and their lean littermates (n=12) were fed 0%, 0.5% or 1% GTE for 6 weeks. Then, hepatic steatosis, oxidative stress and inflammatory markers were measured. Obese mice, compared to lean controls, had greater hepatic lipids and serum alanine aminotransferase (ALT). GTE at 1% lowered (P<.05) hepatic lipids and ALT in obese mice. The GTE-mediated attenuation in hepatic steatosis was accompanied by decreased mRNA expression of adipose sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl CoA desaturase-1, and hormone-sensitive lipase and decreased serum nonesterified fatty acid concentrations. Immunohistochemical data indicated that steatotic livers from obese mice had extensive accumulation of tumor necrosis factor-α (TNF-α), whereas GTE at 1% decreased hepatic TNF-α protein and inhibited adipose TNF-α mRNA expression. Hepatic total glutathione, malondialdehyde and Mn- and Cu/Zn-superoxide dismutase activities in obese mice fed GTE were normalized to the levels of lean littermates. Also, GTE increased hepatic catalase and glutathione peroxidase activities, and these activities were inversely correlated with ALT and liver lipids. Collectively, GTE mitigated NAFLD and hepatic injury in ob/ob mice by decreasing the release of fatty acids from adipose and inhibiting hepatic lipid peroxidation as well as restoring antioxidant defenses and decreasing inflammatory responses. These findings suggest that GTE may be used as an effective dietary strategy to mitigate obesity-triggered NAFLD.     

Purification and characterization of ascamycin-hydrolysing aminopeptidase from Xanthomonas citri.

Intact obese rats were hyperinsulinaemic, had higher rates of whole-body fatty acid synthesis, higher activities of hepatic acetyl-CoA carboxylase and tyrosine aminotransferase and a higher hepatic glycogen concentration than intact lean animals. Adrenalectomy abolished all these factors of the obese phenotype. Treatment of adrenalectomized rats with corticosterone for 24 h increased the rate of whole-body fatty acid synthesis to the same extent in both phenotypes, but caused a larger increase in glycogen concentration, tyrosine aminotransferase activity and plasma insulin concentration in obese rats.     

Lipoprotein secretion in lean and obese Zucker female rats in vivo and in a single-pass-perfused liver preparation

The plasma lipoprotein composition as well as lipoprotein synthesis and secretion were studied in vivo and in a single-pass-perfused liver preparation in lean and obese Zucker rats. Compared with their lean littermates the levels in the plasma of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) + low density lipoprotein (LDL) and high density lipoprotein (HDL) were increased 4-, 2- and 2.5 fold, respectively, in obese rats. In these rats both VLDL and IDL + LDL were enriched in triglycerides, while the HDL were enriched in cholesterol. Although the VLDL and IDL + LDL protein concentrations were the same in lean and obese rats, the HDL protein concentration was 3-fold greater in the obese rats. Both the lean and obese rats incorporated similar amounts of [14C]leucine into total liver protein. However, obese rats incorporated 2.5-fold and 6-fold more [14C]leucine into VLDL and HDL in vivo, 2.7-fold and 1.7 fold more [35S]methionine in VLDL and HDL present in the perfusate, than did lean rats. The perfusate [35S]S-labelled apoproteins (apo-B100, B48; apo-E, apo-AI, apo-AIV and apo-C) were separated by gel electrophoresis and identified by autoradiography. Incorporation of [3H]glycerol into liver, VLDL, IDL + LDL and HDL triglycerides was 2-, 48-, 13- and 1.5-fold higher in obese than in lean rats, respectively. The [3H]-labelled triglycerides in VLDL and IDL + LDL present in the perfusate was 5.4-fold and 4.4-fold more in obese rat. There was no difference in the incorporation of [3H]glycerol into triglycerides of perfusate HDL between the two genotypes of rats. Thus, the hypertriglyceridaemia observed in obese Zucker rats results from very high synthetic rates of both the lipid and protein moieties of plasma lipoproteins. Before this study, no report of the simultaneous triglycerides and protein synthesis in vivo and in a single-pass-perfused liver preparations had been reported.