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J M Dietschy

Publications and source records attributed to J M Dietschy.

At least 55 records · Page 3Linked to original sources
PubMed1993

The interaction of dietary cholesterol and specific fatty acids in the regulation of LDL receptor activity and plasma LDL-cholesterol concentrations.

From these brief considerations, it is clear that the steady-state LDL-cholesterol concentration is determined in a powerful way by the interaction of dietary cholesterol and specific fatty acids. There appear to be only a few saturated fatty acids and an even lesser number of unsaturated fatty acids that significantly interact with cholesterol in the liver cell to alter hepatic LDL receptor activity. These effects are uniformly seen in most experimental animals and in humans under circumstances where the experiments are properly designed. Future work is urgently needed to define the metabolic effects of the more unusual fatty acids (e.g., the trans fatty acid) and the more intimate details of how these substances regulate LDL receptor activity in the cell. It is also of considerable importance to extend these studies to the members of the same species that exhibit variable responses to these same dietary lipids. It is now clear that the magnitude of these specific responses to dietary cholesterol and specific fatty acids varies in different individuals with different genetic backgrounds from the same species. Elucidating the reasons for this variability is another area of research of considerable importance to human biology.

Animals↗
PubMed1993

Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids.

Extensive data obtained in both experimental animals and humans demonstrate that steady-state plasma LDL-C concentrations are determined largely by the rate of LDL-C formation, Jt, and the level of LDL-R activity, Jm, located primarily in the liver. An increase in net cholesterol delivery to the liver suppresses Jm, slightly elevates Jt, and modestly raises the LDL-C level. Feeding lipids such as the 12:0, 14:0, and 16:0 saturated fatty acids further suppresses Jm, increases Jt, and markedly elevates the plasma LDL-C concentration. Feeding triacylglycerols containing the 18:1(c9) fatty acid restores hepatic receptor activity, decreases Jt, and modestly reduces the concentration of LDL-C in the plasma. The 18:2(c9, c12) compound has similar effects, although it is quantitatively less active than the monounsaturated fatty acid in restoring Jm. In contrast to these fatty acids that actively raise or lower hepatic receptor activity, a large group of compounds including the 4:0, 6:0, 8:0, 10:0, 18:0, and 18:1(t9) fatty acids have no demonstrable effect on any parameter of LDL-C metabolism. These fatty acids, therefore, can be added to animal and human diets with relative impunity. They will alter plasma LDL-C levels only to the extent that they replace the active saturated fatty acids (in which case they lower the LDL-C concentration) or unsaturated compounds (in which case they raise the plasma cholesterol level). All of these effects of cholesterol and the various fatty acids can be explained by the effects of these lipids in altering the size of the regulatory pool of cholesterol in the hepatocyte. However, many aspects of the cellular and molecular biology of these regulatory processes require additional investigation. In particular, new studies should focus on how the genetic background of an individual animal or human alters the quantitative response of its plasma LDL-C concentration to the dietary challenge of each of these types of lipids.

Animals↗
PubMed1992

Fatty acids regulate hepatic low density lipoprotein receptor activity through redistribution of intracellular cholesterol pools.

When the intake of dietary cholesterol in the hamster is constant, feeding the saturated 14:0 fatty acid (n-tetradecanoic acid) elevates the plasma low density lipoprotein (LDL) cholesterol concentration from 72 to 204 mg/dl, while the monounsaturated 18:1 fatty acid (cis-9-octadecenoic acid) lowers this level to 28 mg/dl. The 14:0 fatty acid lowers the hepatic cholesteryl ester concentration from 12 to 5 mg/g, while the abundance of this fatty acid in the ester fraction is increased 13-fold. Hepatic LDL receptor activity is depressed to 41% of control, while the LDL cholesterol production rate is increased to 132%. These changes account for the 3-fold increase in the plasma LDL cholesterol concentration. In contrast, feeding the 18:1 fatty acid increases hepatic cholesteryl ester concentration to 21 mg/g, and the abundance of this acid in the esters is increased 1.4-fold. Hepatic receptor activity is increased to 145%, while the production rate is suppressed to 68% of control. These changes account for the decrease in plasma LDL cholesterol level to 28 mg/dl. Despite these marked changes in LDL metabolism, however, the 14:0 and 18:1 fatty acids cause no change in net cholesterol balance across the liver. These results suggest that there are two fundamentally different mechanisms regulating hepatic LDL metabolism. One involves changes in net sterol balance across the liver brought about by alterations in the rate of cholesterol or bile acid absorption across the intestine, while the second is articulated through a redistribution of the putative sterol regulatory pool within the hepatocyte that is dictated by the type of long-chain fatty acid that reaches the liver.

Animals↗
PubMed1992

Regulatory effects of the saturated fatty acids 6:0 through 18:0 on hepatic low density lipoprotein receptor activity in the hamster.

The plasma concentration of cholesterol carried in low density lipoproteins is principally determined by the level of LDL receptor activity (Jm) and the LDL-cholesterol production rate (Jt) found in animals or man. This study delineates which saturated fatty acids alter Jm and Jt and so increase the plasma LDL-cholesterol level. Jm and Jt were measured in vivo in hamsters fed a constant level of added dietary cholesterol (0.12%) and triacylglycerol (10%), where the triacylglycerol contained only a single saturated fatty acid varying in chain length from 6 to 18 carbon atoms. After feeding for 30 d, the 12:0, 14:0, 16:0, and 18:0 fatty acids, but not the 6:0, 8:0, and 10:0 compounds, became significantly enriched in the liver total lipid fraction of the respective groups fed these fatty acids. However, only the 12:0, 14:0, and 16:0 fatty acids, but not the 6:0, 8:0, 10:0, and 18:0 compounds, suppressed Jm, increased Jt, and essentially doubled plasma LDL-cholesterol concentrations. Neither the 16:0 nor 18:0 compound altered rates of cholesterol synthesis in the extrahepatic organs, and both lowered the hepatic total cholesterol pool. Thus, the different effects of the 16:0 and 18:0 fatty acids could not be attributed to a difference in cholesterol delivery to the liver. Since these changes in LDL kinetics took place without an apparent alteration in external sterol balance, the regulatory effects of the 12:0, 14:0, and 16:0 fatty acids presumably are mediated through some change in a putative intrahepatic regulatory pool of sterol in the liver.

Animals↗
PubMed1992

Saturated and unsaturated fatty acids independently regulate low density lipoprotein receptor activity and production rate.

These studies examine the regulation of plasma low density lipoprotein (LDL)-cholesterol levels by varying quantities of dietary saturated and polyunsaturated triacylglycerols. At a constant load of 0.12% cholesterol and 20% triacylglycerol, substitution of polyunsaturated for saturated triacylglycerols caused LDL receptor activity to increase from 25% to 80% of control and reduced the LDL-cholesterol production rate from nearly 200% to 155%. These changes caused the plasma LDL-cholesterol concentration to decrease from nearly 190 to 50 mg/dl. When the dietary content of each triacylglycerol alone was incrementally increased, the saturated lipid suppressed receptor activity while the polyunsaturated triacylglycerol increased receptor-dependent LDL transport. The magnitude of these effects was quantitatively similar, although oppositely directed. However, the saturated triacylglycerol also caused a dose-dependent increase in the LDL-cholesterol production rate and markedly increased the plasma LDL-cholesterol level while the polyunsaturated lipid did not affect either of these. These independent effects were also evident in experiments where it was found that substituting polyunsaturated triacylglycerol for saturated lipid increased receptor activity significantly more than did simply reducing the dietary content of saturated triacylglycerol. Thus, these studies show that triacylglycerols containing saturated or polyunsaturated fatty acids have effects on the major processes that regulate the plasma LDL-cholesterol level that are qualitatively and quantitatively distinct.

Animals↗
PubMed1991

Cholesterol-lowering action of psyllium mucilloid in the hamster: sites and possible mechanisms of action.

These studies were undertaken to examine and compare the metabolic effects of psyllium mucilloid and two other nonabsorbable polymers (cholestyramine and surfomer) on sterol metabolism in the hamster. These three agents all significantly lowered the plasma total cholesterol concentration and the level of cholesterol carried in low-density lipoproteins (LDL). Rates of cholesterol synthesis were markedly increased in the livers of the psyllium-fed animals, but not in other tissues. In contrast, cholestyramine and surfomer feeding increased both hepatic and intestinal sterol synthesis. When cholesterol and saturated triacylglycerols were added to the diet, psyllium feeding essentially completely blocked the increase in the plasma cholesterol concentration and hepatic cholesterol content and the suppression of cholesterol synthesis. The pool of bile acid in the small intestine was increased from the control value (17.9 mumol/animal) by both psyllium (23.0 mumol) and cholestyramine (21.9 mumol) feeding. However, this pool was readily absorbed and secreted into the bile in the psyllium-fed animals (27.9 mumol/4 h), but not in the cholestyramine-treated hamsters (13.0 mumol/4 h). This was consistent with the further observation that there was no binding of bile acid by psyllium under in vitro conditions. Thus, these findings indicate that all three polymers lower plasma cholesterol concentrations by inducing a net negative cholesterol balance across the liver. With psyllium, this effect is presumably articulated through a reduction in cholesterol absorption, as well as an increase in the rate of degradation of cholesterol to bile acids.

Animal Feed↗
PubMed1990

LDL cholesterol: its regulation and manipulation.

Elevated plasma LDL cholesterol concentrations result primarily from two mechanisms: LDL overproduction and loss of hepatic receptor-dependent LDL removal. This knowledge can be used to lower plasma cholesterol and thereby retard or even reverse atherosclerosis. Pharmacologic agents are useful, as are dietary approaches.

Arteriosclerosis↗
PubMed1989

Mechanisms by which saturated triacylglycerols elevate the plasma low density lipoprotein-cholesterol concentration in hamsters. Differential effects of fatty acid chain length.

These studies were designed to elucidate how shorter (MCT) and longer (HCO) chain-length saturated triacylglycerols and cholesterol interact to alter steady-state plasma LDL-cholesterol levels. When either MCT or HCO was fed in the absence of cholesterol, there was little effect on receptor-dependent LDL transport but a 36-43% increase in LDL-cholesterol production. Cholesterol feeding in the absence of triacylglycerol led to significant suppression of receptor-dependent LDL transport and a 26-31% increase in LDL-cholesterol production. However, when the longer chain-length saturated triacylglycerol was fed together with cholesterol there was a marked increase in the suppression of receptor-dependent LDL transport and an 82% increase in production rate. Together, these two alterations accounted for the observed eightfold increase in plasma LDL-cholesterol concentration. In contrast, feeding the shorter chain-length saturated triacylglycerol with cholesterol actually enhanced receptor-dependent LDL transport while also causing a smaller increase (52%) in the LDL-cholesterol production rate. As a result of these two opposing events, MCT feeding had essentially no net effect on plasma LDL-cholesterol levels beyond that induced by cholesterol feeding alone.

Animals↗
PubMed1989

Inappropriate hepatic cholesterol synthesis expands the cellular pool of sterol available for recruitment by bile acids in the rat.

These studies test the hypothesis that a major determinant of excessive biliary cholesterol secretion is a level of hepatic sterol synthesis that is inappropriately high relative to the needs of the liver cell for preserving cholesterol balance. Biliary cholesterol secretion was measured in vivo in two models after loading the hepatocyte with sterol by two different mechanisms. In the first model, cholesterol was delivered physiologically to the liver in chylomicron remnants. This resulted in a sixfold increase in cholesteryl ester content and marked suppression of cholesterol synthesis, but biliary cholesterol secretion remained essentially constant. In the second model, 3-hydroxy-3-methyl-glutaryl CoA reductase levels in the liver were markedly increased by chronic mevinolin (lovastatin) administration. Withdrawal of the inhibitor resulted in a sudden fivefold increase in the rate of sterol synthesis in the liver of the experimental animals that was inappropriately high for cellular needs. This excessive synthesis, in turn, was accompanied by a fivefold increase in the cholesteryl ester content, enrichment of microsomal membranes with cholesterol and, most importantly, by a threefold increase in the rate of biliary sterol secretion. As the rate of sterol synthesis gradually returned to normal over 48 h, the cholesterol ester content, the lipid composition of the microsomal membranes, and rate of cholesterol secretion into bile also returned to baseline values. These results further support the concept of functional compartmentalization of cholesterol in the hepatocyte. Derangements that cause an inappropriately high rate of sterol synthesis in the endoplasmic reticulum may lead to an expansion of that pool of cholesterol that is recruitable by bile acids and, hence, to greater situation of the bile.

Animals↗
PubMed1989

Interaction of aging and dietary fat in the regulation of low density lipoprotein transport in the hamster.

These studies were undertaken to examine the effect of aging on low density lipoprotein (LDL) metabolism in the male hamster. When the hamsters were maintained on a low-cholesterol, low-triglyceride diet, rates of LDL transport in the various tissues of the body and plasma LDL-cholesterol concentrations remained constant over the entire life span (1-24 months) of the hamster. In contrast, rates of de novo cholesterol synthesis fell 50-97% in the various tissues of the body during the transition from rapid body growth in the young animal to the stable adult size. Thus, changes in tissue requirements for cholesterol over the life span of these animals were met by an appropriate adjustment in the rate of de novo synthesis rather than by alterations in LDL transport. When animals were fed a diet enriched in cholesterol and saturated triglycerides, rates of LDL production increased, total body LDL receptor activity was suppressed, and plasma LDL-cholesterol levels rose. Older animals, however, were not more susceptible than young animals to the detrimental effects of these dietary fats. These studies support the view that aging per se has not effect on LDL transport by the liver or other tissues. Rather, the progressive rise in plasma LDL-cholesterol levels seen in Western man is likely due to the consumption of a diet enriched in cholesterol and saturated triglyceride which increases the LDL-cholesterol production rate and suppresses receptor-dependent LDL transport.

Aging↗
PubMed1989

A rapid method to assess the hydrophobicity of the intestinal microvillus membrane in vivo.

Absorption rates for many biologically important compounds are determined by the relative hydrophobicity of the jejunal microvillus membrane. An estimate of this parameter may be obtained by measuring the incremental change in free energy that occurs when a methylene group partitions into the bilayer form an external aqueous solution. Although sensitive, this measurement has been difficult to quantitate in vivo; therefore, these studies have historically been performed in vitro. We describe a rapid, simple technique to measure this parameter in vivo. Furthermore, this method directly quantitates the resistance of aqueous unstirred layers that lie external to the microvillus membrane.

Animals↗
PubMed1988

Bile salt hydrophobicity influences cholesterol recruitment from rat liver in vivo when cholesterol synthesis and lipoprotein uptake are constant.

These studies were undertaken to characterize the role of bile salt hydrophobicity in determining the rate of cholesterol recruitment from the liver. Using an in vivo rat model in which the acquisition of hepatic cholesterol from chylomicron remnants, low-density lipoproteins, and de novo synthesis was measured and kept constant, it was found that the amount of sterol recruited from the liver cell increased progressively as the liver was probed with a constant infusion of progressively more hydrophobic bile salts. The absolute secretion rate of both cholesterol and phospholipid increased nearly 50% as the hydrophobic index of the bile salts traversing the liver increased from 1.7 to 4.5, but the ratio of cholesterol to phospholipid secreted in bile remained nearly constant. Thus, when cholesterol entry into the hepatocyte via lipoproteins and de novo cholesterol synthesis is constant, the mass of cellular cholesterol recruited into the bile is directly proportional to the hydrophobic-hydrophilic balance of the secreted bile salts.

Animals↗
PubMed1988

A time for change.

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Gastroenterology↗
PubMed1988

Interaction of dietary cholesterol and triglycerides in the regulation of hepatic low density lipoprotein transport in the hamster.

These studies report the effects of dietary cholesterol and triglyceride on rates of receptor-dependent and receptor-independent LDL transport in the liver of the hamster. In animals fed diets enriched with 0.1, 0.25, or 1% cholesterol for 1 mo, receptor-dependent LDL transport in the liver was suppressed by 43, 63, and 77%, respectively, and there were reciprocal changes in plasma LDL-cholesterol concentrations. In addition, dietary triglycerides modified the effect of dietary cholesterol on hepatic LDL transport and plasma LDL concentrations so that at each level of cholesterol intake, polyunsaturated triglycerides diminished and saturated triglycerides accentuated the effect of dietary cholesterol. When animals were raised from weaning on diets containing small amounts of cholesterol, the decline in receptor-dependent LDL transport was nearly abolished by the addition of polyunsaturated or monounsaturated triglycerides, but was markedly augmented by the addition of saturated lipids. When animals raised on diets containing cholesterol and saturated triglycerides were returned to the low cholesterol, low triglyceride control diet, hepatic receptor-dependent LDL transport and plasma LDL-cholesterol concentrations returned essentially to normal within 2 wk. Neither receptor-independent LDL transport nor the receptor-dependent uptake of asialofetuin was significantly altered by dietary cholesterol or triglyceride suggesting that the effect of these lipids on hepatic LDL receptor activity was specific and not due to a generalized alteration in the physiochemical properties of hepatic membranes. These studies demonstrate the important role of saturated triglycerides in augmenting the effect of cholesterol in suppressing hepatic LDL receptor activity and elevating LDL-cholesterol levels.

Animals↗
PubMed1988

Sterol synthesis and low density lipoprotein clearance in vivo in the pregnant rat, placenta, and fetus. Sources for tissue cholesterol during fetal development.

Whereas the greatest relative increase in body mass occurs during the third trimester of fetal life, the source of the cholesterol that supports this growth is uncertain. These studies used [3H]water and 125I-cellobiose-labeled low density lipoproteins to quantitate absolute rates of cholesterol acquisition in vivo by the fetus of the rat. Preliminary studies demonstrated that [3H]water administered intravenously to the mother rapidly equilibrated with the body pool of water in the fetus and that 22-microgram atoms of H from the water pool were incorporated into each micromole of newly synthesized cholesterol. After administration of [3H]water to pregnant rats, the rates of sterol synthesis per 100 g of whole body weight were severalfold higher in the fetus than in the dams. Individual organs of the dam such as the liver, however, had much higher synthetic rates than those in the fetus. When maternal hepatic cholesterol synthesis was suppressed by cholesterol feeding, newly synthesized cholesterol disappeared from the maternal blood yet there was essentially no change in the rate of appearance of newly synthesized sterol in the fetus, placenta, and fetal membranes. The placenta did take up low density lipoproteins at rates equal to about one-third of that seen in the maternal liver, but none of the apolipoprotein or cholesterol was transferred to the fetus. These studies indicate that the rat fetus receives little or no cholesterol from the mother but, rather, satisfies its need for cholesterol during fetal development through local synthesis. Furthermore, the fetal membranes appear to be an important site for sterol synthesis in the fetal compartment.

Animals↗
PubMed1987

Kinetic characteristics and mechanisms of regulation of receptor-dependent and receptor-independent LDL transport in the liver of different animal species and humans.

In the normal animal and in humans, low-density lipoproteins (LDL) are removed from the plasma by both receptor-dependent and receptor-independent transport mechanisms. Most of the receptor-dependent transport activity is found in the liver, whereas the receptor-independent transport process is widely distributed in many organs. In the steady state the plasma LDL-cholesterol concentration is determined by the rate of LDL production, relative to the rate of LDL removal from the vascular space. This rate of removal in turn is determined by three transport parameters: Jm, the maximal transport rate for the receptor-dependent process in the whole animal; Km, the concentration of LDL-cholesterol in the plasma at which half Jm is achieved; and P, the proportionality constant for the receptor-independent transport process. The values of these parameters are now known for several species, including humans and provide the basis for understanding how the plasma LDL-cholesterol concentration is altered by environmental factors such as aging and diet. With aging, for example, there appears to be no change in the receptor-dependent transport process, and in those situations in which the plasma LDL-cholesterol level rises, this increase appears to be caused by overproduction of LDL. With cholesterol feeding the plasma LDL-cholesterol level rises because of an increase in the LDL production rate coupled with a decrease in the maximal transport rate for the receptor-dependent process. The addition of saturated triglycerides to the diet further suppresses the Jm value, whereas unsaturated lipids enhance the maximal transport rate for LDL and lowers the plasma LDL-cholesterol level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗