Transcript 2008 VFA Absorption

VFA Absorption
• References
– Church
– Sjersen
176-177
173-195
• Significance of VFA absorption
– VFA production = 5 moles/kg DM
– 95% of the VFA are absorbed before the
abomasum
– 15% of the VFA (primarily butyrate) do not enter
portal circulation
• VFA absorption is through diffusion and
facilitated transport modified by metabolism
– No active transport
Rumen
HAc
pH
dependent
Ac
HCO3CO2
HAc
HAc
AcTransporters:
Anion exchange,
Putative anion
transport,
Downregulated
In adenoma
Metabolism
(30% Ac, 50% Prop,
90% But)
Aerobic
Anerobic
CO2
Ketones
Carbonic
(Acetoacetate,
anhydrase
B-(OH)-butyrate)
H2CO3
HCO3-
H+
Na+
Portal blood
Epithelium
Lactate
H+
Na+/H+ exchange
Na+
Proton-linked
monocarboxylate
transporter
Na+/H+ exchange
To liver
&
peripheral
tissue
H+
H+
Na+
• Results of VFA absorption and metabolism
– 90% of the circulating VFA is acetate
– 80% of the circulating ketones is B-OH-butyrate
• Some produced from metabolism of acetoacetate in the
liver
• Factors affecting VFA absorption
– VFA concentration in rumen
• 3-fold increase (no change in pH)
– Increases acetate absorption 2-fold
– Increases butyrate absorption 4-fold with no increase
in metabolism
– Chain length
• At pH 7.4, Ac > Prop > But
– pH
• Decreased pH increases VFA absorption
• From pH 7.4 to 6.4
–
–
–
–
No effect on acetate
2-fold increase in propionate
4-fold increase in butyrate
Result: But > Prop > Ac
• Advantages of epithelial metabolism of VFAs
– Provides energy to epithelial cells
• Total viscera requires 25% of the total energy
requirement
• Use of VFAs as an energy source spares glucose
• Relatively minor use
– Aerobic metabolism yields CO2 used for
production of HCO3 needed for acid-base balance
– Reduces concentration gradient to allow more
VFA absorption
– Ketone bodies can bypass liver metabolism and,
thereby, provide energy to peripheral tissues and
C for fatty acid synthesis
– Detoxifies n-butyrate
• Effects of diet on VFA absorption
– Increased proportion of grain in diet
•
•
•
•
Increased VFA production in rumen
Decreased rumen pH
Greater proportion of VFA in undissociated form
Greater size of papillae, number of epithelial cells, and
blood flow
• Upregulation of transport proteins
• Increased VFA metabolism in epithelium
– Only because of increased number of epithelial cells
• Increased VFA absorption by 4-fold
VFA Metabolism
• References
– Church pp 279-290; 286-289
– Ruckebusch pp. 485-500
– Sjersen pp. 249-265; 389-409
• Post-absorption
– Uptake by the liver
• Acetate
– Very little removed by liver
– Most transported to peripheral tissues for
» Oxidation
» Long chain fatty acid synthesis
• Propionate
– 94% of propionate entering liver is metabolized
– Use
» Gluconeogenisis
• Butyrate
– Liver has low affinity for B-OH-butyrate
– Approx 20% of butyrate in rumen is metabolized in
the liver
» Acetoacetate > B-OH-butyrate
– Uses
» Oxidation
» Long chain fatty acid synthesis
– Control of location of VFA metabolism
• Location of specific acyl-CoA synthetases
– Acetate
» Acetyl CoA synthetase
High in peripheral tissues
Low in rumen epithelium and liver
– Propionate
» Propionyl CoA synthetase
Low in rumen epithelium
High in liver
– Butyrate
» Butyryl CoA synthetase
High in rumen epithelium
Present in heart muscle
May also be activitated by medium chain fatty
acid-CoA synthetase in peripheral tissues
• Uses of VFAs
– Maintenance energy
ATP CoA
Acetate
Acetyl CoA
Net/mole
TCA cycle 12 ATP + 2CO2
10
2ATP CoA CO2
Propionate
Succinyl CoA TCA cycle 20 ATP + 4CO2 18
2ATP CoA
Butyrate
Acetyl CoA
5 ATP
TCA cycle
24 ATP + 4CO2
27
– Efficiency of VFAs for energy metabolism
Mole ATP
Heat of
Mole acid Efficiency
/mole Efficiency
combustion produced
of
acid
of
VFA
kcal/mole /glucose Fermentation oxidized combustion
Acetate
209.4
2
62.2
10
34.8
(209.4 x 2
(7.3 x 10
/673)
/209.4)
Propionate
367.2
2
109.1
18
35.8
Butyrate
524.3
1
77.9
27
37.6
Glucose
673
38
41.2
____________________________________________________________
• Implications
– Little difference in efficiency of use of Acetate,
Propionate and Butyrate over a wide range of
concentrations
– Balance is required between VFAs for efficient use
– Difference in total efficiency between different
fermentation types is associated with the efficiency of
fermentation
– Gluconeogenesis
• Glucose requirements
– Central nervous system
» 15 – 20% of glucose utilization
– Pregnancy
» For fetus
– Lactation
» Lactose synthesis
– Lipid synthesis
» NADPH for fatty acid synthesis
» Glycerol
– Precursors for gluconeogenesis
Precursor
Propionate
Amino acids
(Primarily Alanine,
Glutamine, Glutamate)
Lactate
Glycerol
% of Glucose from:
Fed
Fasted
40 – 60
0
15 – 30
35
15
5
40
25
– Mechanism of gluconeogenesis
– Controlling enzymes
• Pyruvate carboxylase
(Pyr > OAA)
• NAD-malate
dehydrogenase
(Mal > OAA)
• PEP carboxykinase
(OAA > PEP)
• Fructose-1,6diphosphatase
(Fru-1,6-P > Fru-6-P)
• Glucose-6-phosphatase
(Glu-6-P > Glu)
– Hormones
• Glucagon and Glucorticoids
• Insulin
– Glucose conservation
• Low blood glucose
• Low hexokinase activity in the liver
• Little glucose used for long chain fatty acid synthesis in
ruminants
– Fatty acid synthesis
• Locations
– Nonlactating animals
» 92% of fatty acid synthesis is in adipose tissue
and 6% is in the liver
– Lactating animals
» 40% of fatty acids in milk fat are synthesized in
mammary gland
• Why glucose is not a Csource for fatty acid
synthesis
– Limiting enzymes
– Bauman
Citrate lyase
Malate
dehydrogenase
– Baldwin
Pyruvate kinase
Pyruvate
dehydrogenase
– Use of glucose for fat
synthesis
• Supply NADPH
• Synthesis of glycerol
– Precursors for fatty acid synthesis in ruminants
• Acetate
– 75 – 90% of C in C4 – C14 fatty acids
– 20% of C in palmitate (C16)
– 0% of C in C18
• Butyrate
– Acetate and B(OH)butyrate contribute equally to the
first 4 carbons
– Must be converted to acetyl CoA for additional C
• Lactate
– 5 – 10% of the fatty acids in milk
– Inversely related to the amount of acetate available
» Controlled by pyruvate dehydrogenase
– Additional uses of lactate
» Glycerol
» NADPH from Isocitrate cycle
• Propionate
– Precursor for odd and branched chain fatty acids
– Increased by increased concentration of methylmalonyl
CoA from vitamin B12 deficiency
• Energy partitioning between adipose and
milk fat
– High grain diets with deficient eNDF will result in
reduction in milk fat synthesis and increase
adipose tissue
– Insulin-glucogenic theory
•
•
•
•
Increases propionate and reduces acetate production
Increases glucose synthesis
Increases insulin secretion
Increases glucose uptake by adipose tissue, but not
mammary gland
• Increases NADPH synthesis in adipose tissue
• Increases fatty acid synthesis in adipose tissue, making
less acetate available for mammary gland
• Now believed that insulin plays a minor role in milk fat
depression
– Biohydrogenation theory
• High grain diets, diets with deficient eNDF, or diets high
in polyunsaturated fatty acids
– Increase production of trans-10, cis-12 conjugated
linoleic acid (CLA)
Linoleic acid
(cis-9, cis-12 C18:2)
High forage
Conjugated linoleic acid
(cis-9, trans-11 CLA)
High grain
Conjugated linoleic acid
(trans-10, cis-12 CLA)
Vaccenic acid
(trans-11 C18:1)
trans-10 C18:1
Stearic acid
C18:0
Stearic acid
C18:0
– Even at low doses (<5 g/d), trans-10, cis-12 CLA
inhibits fat synthesis in mammary gland
• Mechanism
– trans-10, cis-12 CLA inhibits migration of Sterol
Response Element-Binding Protein (SREBP)
transcriptional factor to the nucleus of mammary
cells
– Results in reduction in mRNA for genes involved in:
» Fatty acid uptake
Lipoprotein lipase
» Fatty acid transport
Fatty acid binding protein
» Fatty acid synthesis
Acetyl CoA carboxylase
Fatty acid synthase
» Fatty acid desaturation
Stearoyl-CoA desaturase
» Triglyceride synthesis
Acylglycerol phosphate acyl transferase
Glycerol phosphate acyl transferase