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Triglyceride Uptake and Lipoprotein Lipase–Generated Fatty Acid Spillover in the Splanchnic Bed of Dogs

¹ Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
² Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, Tennessee

Address correspondence and reprint requests to John M. Miles, MD, Endocrine Research Unit, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. E-mail: miles.john{at}mayo.edu

Abbreviations: FFA, free fatty acid; HPLC, high-performance liquid chromatography; HSL, hormone-sensitive lipase; LPL, lipoprotein lipase

	ABSTRACT

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 
The action of lipoprotein lipase on triglyceride-rich lipoproteins generates fatty acids that are either transported into tissues or mix with circulating free fatty acids (FFAs) via a process known as spillover. In the present study, arterial, portal vein, and hepatic vein sampling catheters were surgically placed in nine mongrel dogs. The animals were subsequently studied after a 42-h fast during infusion of [¹⁴C]oleate and a lipid emulsion containing [³H]triolein; the emulsion was used as a surrogate for the study of chylomicron metabolism. More than one-half of splanchnic [³H]triglyceride uptake occurred in the liver, and substantial fractional spillover of [³H]oleate was observed in both liver and nonhepatic tissues (50% each). There was a significant correlation between FFA release from nonhepatic tissues (presumably visceral fat) and nonhepatic fractional spillover (R = 0.81, P < 0.01), consistent with a model in which the rate of intracellular lipolysis influences spillover by determining the direction of net fatty acid flow between the cell and the interstitium. There was a significant correlation between "true" and "net" splanchnic spillover (R = 0.84, P < 0.005), the latter representing calculation of spillover between arterial and hepatic venous blood without portal venous data. Metabolism of chylomicron triglycerides in visceral fat may be an important source of portal venous FFAs.

The mechanisms by which dietary fat is stored are incompletely understood. Fat absorption itself is essentially quantitative (1), but evidence has accumulated that the subsequent storage of triglyceride fatty acids from circulating chylomicrons, mediated by lipoprotein lipase (LPL), is variably efficient. The process by which some LPL-generated fatty acids escape into the venous effluent from tissues and mix with systemic free fatty acids (FFAs) has been referred to as "spillover" and has been measured systemically (2–4) and in regional tissue beds (2,3). The degree of spillover that occurs may vary in relation to the temporal distance from a previous meal (5) and perhaps other factors.

Visceral fat is a major site of dietary fat storage (6) and also a potential significant contributor to portal vein FFA concentrations because of active visceral lipolysis mediated primarily by hormone-sensitive lipase (HSL), lipolysis that is increased in individuals with visceral obesity (7). Increased FFA delivery to the liver via the portal vein may be an important cause of hepatic insulin resistance (8) and increased production of VLDLs in that tissue (9).

At present, relatively little information is available regarding spillover of LPL-generated FFA in visceral adipose tissue. The present study was conducted to determine the extent of spillover in nonhepatic splanchnic tissues and in the liver.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

 
Animals and surgical procedures.
Nine adult mongrel dogs (average weight 22.2 kg) were studied after a 42-h fast. The animals’ care was in accordance with National Institutes of Health guidelines for the care and use of laboratory animals. The protocol was approved by the Vanderbilt University Institutional Animal Care and Use Committee.

Each dog underwent a laparotomy under general anesthesia 14–16 days before the experiment. Catheters (0.04-inch internal diameter) for blood sampling were placed into the left hepatic vein, the hepatic portal vein, and left femoral artery as previously described (10), together with transonic flow probes around the portal vein and hepatic artery. All catheters were filled with heparinized saline (200 units/ml; Abbott Laboratories, North Chicago, IL), and their free ends were knotted and then tunneled to a subcutaneous pocket before closure of the skin. The animals were fed standard dog chow and were weight stable before study.

Preparation of tracers.
[1-¹⁴C]oleate (GE Healthcare) was prepared for infusion as previously described (11). A commercial lipid emulsion (10% Intralipid) was labeled with [9,10-³H]triolein (Perkin Elmer) and heat sterilized for infusion (12).

Study protocol.
On the day of study, the blood sampling catheters were exteriorized and carefully aspirated to clear residual heparinized saline. Infusions of [9,10-³H]triolein (1.2 µCi/min) and [1-¹⁴C]oleate (0.3 µCi/min) were started in a peripheral vein 90 and 60 min, respectively, before the first blood samples were taken from the artery, the portal vein, and the hepatic vein. These time frames were chosen to establish tracer equilibrium; the tracer infusions were continued until blood sampling had been completed. The radiolabeled lipid emulsion is of sufficiently high specific activity that it does not affect plasma triglyceride concentrations when infused (2). An arterial blood sample was drawn before the tracer infusions to serve as a blank. Subsequently, five matched arterial, portal vein, and hepatic vein blood samples were taken at 7.5-min intervals for a total of 30 min for measurement of plasma triglyceride radioactivity and FFA concentration and specific activity. Plasma flow was calculated from Doppler probe and hematocrit.

Analyses.
Blood samples were immediately transferred to chilled 10-ml EDTA tubes containing 0.5-mg of paraoxon to inhibit LPL (13) and kept on ice until centrifugation at 4°C. The resulting plasma was then frozen at –70⁰ C until analysis. Modification of a previously published procedure (11) allowed measurement of plasma triglyceride radioactivity, FFA concentration, and specific activity on the same aliquot of plasma. Fifty microliters of 2.0 mmol/l [²H₃₁]palmitate was added to 1.0 ml plasma (14). A lipid extraction was then performed using the method of Dole and Meinertz (15). The organic layer was then back-extracted twice with 0.02 N NaOH to separate FFA from triglyceride radioactivity. The organic layer was dried down under a stream of nitrogen and resuspended in 10 ml Optiflor for determination of triglyceride radioactivity by liquid scintillation counting. Triglyceride radioactivity was corrected for recovery, which averaged 95%, and also for incomplete removal of radiolabeled FFA from the triglyceride fraction, which averaged 5% of FFA radioactivity. The FFA (aqueous) layer was then acidified with 20 µl 3 N HCl, dried under nitrogen, and derivatized as previously described for analysis of FFA using high-performance liquid chromatography (HPLC) (11). The HPLC method was modified for measurement of total FFA using a 15-cm 4µm Waters C18 Nova-Pak column eluted with 78% acetonitrile in water and connected to a Waters 2487 UV detector (260 nm). With this modification, oleate elutes at 14–15 min. The oleate peak was collected for measurement of [³H] and [¹⁴C] radioactivity by liquid scintillation spectrometry. Baseline arterial plasma triglyceride concentrations in each animal were determined using a Sigma TR0100 kit.

Calculations.
All calculations were made using steady-state assumptions. Systemic spillover of triglyceride-derived oleate (estimated from [³H]oleate generation) was calculated from oleate concentrations, [³H] specific activities and [¹⁴C] specific activities in arterial plasma, as previously described (2). The availability of portal venous blood sampling in this study allowed the separate determination of spillover in two components of the splanchnic bed: the liver and nonhepatic tissues. A cartoon depicting the mathematical basis for estimating spillover in tissue beds is shown in the online appendix (available at http://dx.doi.org/10.2337/db06–1657).

Net splanchnic kinetics.
Net splanchnic spillover was calculated from the following formulas, which do not take the portal venous circulation into consideration. These formulas use arterial and hepatic venous values, analogous to determination of spillover in the human forearm (2).

Net fractional extraction of oleate for the splanchnic bed was calculated from the formula

(1)

where SA is specific activity, C is concentration, and subscripted A and H refer to arterial and hepatic venous plasma, respectively.

The net rate of [³H]oleate release in the splanchnic bed that would be expected if there were no local uptake of triglyceride-derived oleate (i.e., if fractional spillover were 100%) was calculated from the uptake of [³H]triglyceride from arterial plasma according to the formula

(2)

where [³H] TG equals the concentration of [³H]triglyceride in dpm · mL^–1, PF_P equals portal venous plasma flow, and PF_A equals hepatic artery plasma flow.

The actual net release of triglyceride-derived [³H]oleate in the splanchnic bed was calculated from the formula

(3)

where the expression ([³H]SA_A x C_A x [1-FE_S]) equals the predicted concentration of [³H]oleate in hepatic venous plasma if fractional spillover of triglyceride-derived oleate is zero.

Nonhepatic splanchnic tissue kinetics.
Fractional extraction of oleate for nonhepatic splanchnic tissues was calculated from the formula

(4)

The rate of [³H]oleate release in nonhepatic splanchnic tissues that would be expected if there were no local uptake of triglyceride-derived oleate (i.e., if fractional spillover were 100%) was calculated from the uptake of [³H]triglyceride from arterial plasma according to the formula

(5)

The actual release of triglyceride-derived [³H]oleate in nonhepatic splanchnic tissues was calculated from the formula

(6)

Hepatic kinetics.
Hepatic spillover was calculated from the following formulas, which take into account that organ's dual blood supply.

Fractional extraction of oleate for the liver was calculated from the formula

(7)

The rate of [³H]oleate release in the liver that would be expected if there were no local uptake of LPL-generated oleate was calculated as follows:

(8)

The actual release of triglyceride-derived [³H]oleate in the liver was calculated from the formula

(9)

Spillover calculations.
Fractional spillover of [³H]oleate for the splanchnic bed, nonhepatic tissues, and the liver was calculated by the formula

(10)

using the respective R and E values for the three tissue beds.

"True" fractional spillover for the splanchnic bed was calculated from nonhepatic splanchnic and hepatic spillover, the contribution from each tissue bed weighted for the relative distribution of spillover in the two tissue beds:

(11)

Nonsplanchnic spillover was calculated from the difference between systemic and true splanchnic [³H]triglyceride uptake and [³H]oleate appearance. The contribution of nonhepatic splanchnic and hepatic tissues to systemic [³H]triglyceride disappearance was calculated by dividing [³H]triglyceride uptake (equal to ER_NH and ER_H, respectively, in Eqs. 5 and 8 above) by the [³H]triolein infusion rate. Because whole plasma triglyceride radioactivity was measured, an estimate of the contribution of hepatic extraction of labeled emulsion remnants to total hepatic extraction of labeled triglyceride was made. Based on the half-life of large emulsion particles and remnants, this contribution was estimated to be 0.8%. A detailed description of this calculation is provided in the online appendix.

Systemic oleate and FFA flux was calculated as previously described (16). Oleate uptake and release were calculated for the liver and for nonhepatic splanchnic tissues as previously described in dogs (17) and extrapolated to total FFA uptake and release using the ratio of total FFA:oleate concentrations (16). The contribution of nonhepatic and hepatic tissues to systemic oleate uptake and release was determined by dividing oleate uptake and release by systemic oleate flux.

Statistics.
Data are expressed as means ± SE. Mean values were calculated by averaging results from the five samples taken from each site. Comparisons between site values in the group of subjects were analyzed by a t test for paired samples for means using the Excel (Microsoft) data analysis package. Correlations were tested for significance using Pearson's correlation coefficient. The relationship between net and true splanchnic spillover was tested for significance with Spearman's rank correlation coefficient, using JMP 6.0.0 by SAS Institute. A P value of <0.05 was required for statistical significance in all cases.

	RESULTS

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A total of 11 animals were studied, but usable data were available on only 9, because steady-state conditions were not achieved in two of the animals. Baseline arterial plasma triglyceride concentrations were 65 ± 6 mg/dl (data not shown). Plasma [³H]triglyceride concentrations are shown in Fig. 1. Portal venous [³H]triglyceride levels (7,545 ± 882 dpm/ml) were significantly lower than arterial (8,609 ± 1,081 dpm/ml) (P = 0.001). Hepatic venous concentrations (6,493 ± 1,008 dpm/ml) were lower than both arterial and portal venous values (P < 0.01). Fractional extraction of [³H]triglyceride was 26.0 ± 3.5% for the total splanchnic bed, 11.8 ± 1.3% for nonhepatic tissues, and 17.7 ± 4.3% for the liver. Plasma total FFA and oleate concentrations are shown in Table 1 together with plasma oleate specific activities. Portal venous oleate and FFA concentrations were higher than arterial (374 ± 36 and 934 ± 74 vs. 329 ± 30 and 825 ± 68 µmol/l, respectively, both P 0.02). Hepatic venous oleate and FFA concentrations (305 ± 26 and 755 ± 55 µmol/l, respectively) were lower than both arterial (P < 0.01) and portal (P < 0.001) concentrations. Portal and hepatic [¹⁴C]oleate specific activities were lower than arterial (2.10 ± 0.25 and 2.14 ± 0.23, respectively, vs. 2.47 ± 0.30 dpm/nmol (P 0.01 for both comparisons). [³H]oleate specific activity was higher in the hepatic vein than either the artery or portal vein (8.57 ± 0.69 vs. 7.03 ± 0.58 and 7.04 ± 0.0.68 dpm/nmol, respectively; P < 0.005 for both).

View larger version (8K): [in this window] [in a new window]   FIG. 1. Triglyceride radioactivity in arterial, portal venous, and hepatic venous blood.

View larger version (41K): [in this window] [in a new window]   FIG. 2. Systemic, nonsplanchnic, splanchnic, nonhepatic splanchnic, and hepatic fractional spillover.

View larger version (8K): [in this window] [in a new window]   FIG. 3. Relationship between net splanchnic spillover and true splanchnic spillover.

View larger version (9K): [in this window] [in a new window]   FIG. 4. Relationship between FFA release and spillover in nonhepatic splanchnic tissues.

	DISCUSSION

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION REFERENCES

There was a strong correlation between fractional spillover and FFA release in nonhepatic splanchnic tissues in this study. Presumably, these two processes reflect LPL and HSL activity, respectively, in visceral adipose tissue. A link between spillover and FFA release has not previously been demonstrated. It is possible that the net flow of fatty acids may be governed by the concentration gradient between adipose tissue and the extracellular fluid. A graphic model of this process is shown in Fig. 5. In the fed state, intracellular lipase activity is low, and the flow gradient is inward, promoting efficient uptake of LPL-generated fatty acids. Presumably, the vast majority of these fatty acids taken up by adipose tissue are directed toward esterification and ultimately triglyceride storage. In the fasting state, intracellular lipase activity is higher, and the gradient of flow tends to be outward, promoting spillover. Such a reciprocal relationship between intracellular lipolysis and the efficiency of LPL-mediated fat storage would not necessarily mean that the direction of fatty acid flow is the only factor that affects spillover.

View larger version (18K): [in this window] [in a new window]   FIG. 5. Proposed model describing relationship between intracellular lipase activity and fractional spillover of LPL-generated fatty acids in adipose tissue in the fed (A) and fasted (B) states. TG, triglyceride; TGRL, TG-rich lipoprotein; FAT, fatty acid transporter.

Net splanchnic spillover in our study was calculated from arterial and hepatic venous data, without measurements from the portal vein. There was a significant correlation (P < 0.005) between net spillover and true spillover. Also, net spillover was somewhat lower than "true" spillover (calculated as the average spillover in nonhepatic tissues and the liver when portal venous measurements were used), although the difference did not reach statistical significance. This indicates that measurement of net spillover in humans, where access to the portal vein is not possible, could provide significant underestimates of true events.

Nonhepatic spillover correlated significantly with portal venous FFA concentrations. Although it has previously been shown that subcutaneous, not visceral lipolysis, is the chief source of FFA in the portal vein (7), this correlation may be the consequence of a strong linkage between subcutaneous and visceral lipolysis.

In this study, visceral lipolysis (i.e., nonhepatic splanchnic FFA release) accounted for 19% of hepatic FFA delivery. This is a somewhat higher proportion than reported in an earlier study (17) of 18-h–fasted dogs (11%); the discrepancy between the two studies likely relates to the fact that the animals in the present study had been fasted for 42 h and, as a result, had higher plasma FFA concentrations than 18-h–fasted dogs.

The splanchnic bed accounted for nearly one-third of systemic triglyceride uptake in our study. Corrected for spillover, nonhepatic tissues (presumably visceral fat) were responsible for 6% of the systemic disappearance of radiolabeled triglyceride fatty acids. This is very similar to the 8% fractional meal fat disposal in visceral fat previously reported in humans (6) and suggests that the radiolabeled lipid emulsion is metabolized by LPL very similarly to native chylomicrons. We previously reported that infusion of a radiolabeled lipid emulsion accurately detects the absorption of dietary fat (12), which is also consistent with this interpretation.

Redgrave and Maranhao (24) have demonstrated that triglyceride clearance from lipid emulsion particles that lack cholesterol is nearly identical to triglyceride clearance from endogenous chylomicrons in rats; on the other hand, they found that cholesterol content in the emulsion particle is a critical determinant of the metabolic behavior of particle remnants. Another study in dogs strongly supports the usefulness of the radiolabeled lipid emulsion as a surrogate tool in the study of chylomicron triglyceride metabolism. Bergman et al. (20) harvested chylomicrons from donor dogs who had ingested [³H]palmitate and administered the radiolabeled chylomicrons simultaneously with [¹⁴C]palmitate intravenously to recipient postabsorptive dogs, sampling arterial, portal venous, and hepatic venous blood. The authors reported "percent chylomicron uptake released as FFA " analogous to percent spillover. The results of that study using endogenously labeled chylomicrons were very similar to the respective results of the present study in terms of triglyceride fractional extraction in nonhepatic splanchnic tissues (9 vs. 12%), fractional extraction in the liver (22 vs. 18%), nonhepatic splanchnic spillover (48 vs. 50%), and hepatic spillover (39 vs. 45%).

Potential limitations of these data should be acknowledged. It is theoretically possible that radiolabeled oleate could recycle through synthesis and secretion of VLDL triglyceride. However, previous studies in dogs (25) and recent studies in humans (26) indicate that spillover of fatty acids from LPL hydrolysis of VLDL is very low to negligible. The explanation for lower spillover from VLDL compared with chylomicrons is not certain, but it may be related to kinetic differences, considering that LPL has a much higher affinity for chylomicrons compared with VLDL (2,27–29). There is uncertainty regarding whether data obtained in fasting dogs is relevant to the circumstance of meal absorption in humans. It is reassuring that systemic spillover in postabsorptive dogs (49% in the present study) is similar to values of 36–48% previously reported in postabsorptive humans (2,28). A recent study indicates that spillover in human adipose tissue ranges from 13% at 1 h to 52% at 6 h after meal ingestion (29).

In summary, there is significant spillover of fatty acids derived from circulating triglycerides in nonhepatic splanchnic tissues and in the liver in 42-h–fasted dogs. In nonhepatic tissues, which presumably represent visceral fat, spillover correlates with lipolysis or the release of FFA into the portal vein. Thus, efficient storage of dietary fat may require adequate suppression of adipose tissue lipolysis, which typically depends on the antilipolytic effects of the increased insulin concentrations that are observed after meal ingestion. Considering that the amount of dietary fat that traverses the circulation can be similar to systemic FFA flux (2), the contribution of spillover of fatty acids from chylomicrons to total portal FFA is of major potential importance. Abnormally high spillover rates in visceral fat could contribute to both hepatic insulin resistance and increased VLDL triglyceride production by raising postprandial portal venous FFA concentrations (9,30). Ultimately, the relevance of our observations in fasted dogs to meal fat disposal is uncertain and will require further study.

	ACKNOWLEDGMENTS

 
This study has received support from the U.S. Public Health Service (Grants HL67933 and DK18243) and from the Mayo Foundation.

We thank Tiffany Rodewald, Doss Neal, and Danielle Vlazny for technical assistance.

	FOOTNOTES

 
Published ahead of print at http://diabetes.diabetesjournals.org on 6 April 2007. DOI: 10.2337/db06-1657.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1657.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication November 27, 2007 and accepted in revised form March 29, 2007

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This Article Abstract Full Text (PDF) Online-Only Appendix All Versions of this Article: db06-1657v1 56/7/1850    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nelson, R. H. Articles by Miles, J. M. Search for Related Content PubMed PubMed Citation Articles by Nelson, R. H. Articles by Miles, J. M. Social Bookmarking                What's this?