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HEPAGEN

• Metabolic Management of Cow Health

Roberto Farina - Fatro
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Metabolic Management of Cow Health

• Cow metabolism during transition
• Fatty liver and related disorders
• Transcriptional control of lipid/energy
  metabolism PPARs
• PPAR-alpha agonists in veterinary

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The Transition Period
The last 3 wk before to 3 wk after parturition
Extreme CHALLENGE
Pregnant Nonlactating
Nonpregnant Lactating

• Tremendous metabolic adaptations to support
  lactation
• Most diseases occur during or soon after this
  time

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Hepatic Adaptation to Lactation
Prepartum Postpartum Increase
Hepatic Blood Flow 1140 l/h 2099 l/h 84
DMI 9.8 kg/d 14.1 kg/d 44
Liver Oxygen Utilization 1619 mmol/h 3159 mmol/h 95
Daily Metabolic Activity per gram of liver 4.4 mmol O2/g 8.6 mmol O2/g X 2
Glucose Release from Liver 1356 g/d 2760 g/d X 2
Big changes over a very short time highlight the
tremendous metabolic adaptations necessary to
adequately support lactation
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Energy intake and requirements for a lactation
in dairy cows
Mcal/day
After parturition extra energy requirement for
milk production is not met by feed energy intake
Negative Positive
Lipolisis
Energy Balance Energy Ingested - Energy Required
DIM
Parturition
Adapted from Bauman and Currie 1980
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Lipid Metabolism during NEB
Adipose Tissue
? epinephrine
NEB
HSL
? Insulin
Lipolisis
CO2
Liver
CO2
Muscles Udder
ß-oxidation
KB
KREBS
TG
CO2
NEFA
CO2
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Blood NEFA and Liver TG around calving
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Incidence of fatty liver in dairy cows
Fatty liver is a common condition, up to 50 of
dairy cows
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Consequences of Fatty Liver
The Liver sits at the crossroads of
metabolism Its integrity is vital to all
physiological processes
Fatty liver has detrimental effects on health,
productivity and fertility
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Association of fatty liver with health status
Disorder Association Reference
Displaced abomasum Wada et al., 1995 Rehage et al., 1996
Impaired immunoreactivity Wentink et al., 1997 Zerbe et al., 2000
Ketosis Gröhn et al., 1987 Veenhuizen et al., 1991
Laminitis Fronk et al., 1980 Rehage et al., 1996
Mastitis Morrow et al., 1979
Metritis Haraszti et al., 1982 Heinonen et al., 1987
Milk fever Higgins and Anderson, 1983 Gröhn et al., 1987
Retained placenta Haraszti et al., 1982 Heinonen et al., 1987
Bobe 2004
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Association of Fatty Liver with impairment of the
immune system
Mastitis incidence (30 days)
Hepatic fat increment (2 wk after vs. 2 wk before
calving)
Curtis 1989
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Association of fatty liver with reproductive
performance
Parameter Association Reference
First ovarian activity Reid et al., 1983 Rukkwamsuk et al., 1999c
First ovulation Reid et al., 1983
First estrus Paulová et al., 1990 Jorritsma et al., 2000
First insemination Reid et al., 1983
Days open Heinonen et al., 1987 Paulová et al., 1990
Pregnancy rate Haraszti et al., 1982 Jorritsma et al., 2000
Services/cow Schäfer et al., 1988 Paulová et al., 1990
Bobe 2004
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PPARs

• Regulation of Lipid Metabolism

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Metabolism Regulation

• All the cells regulate their metabolism in
  response to changes in the environment and
  metabolize fuels according to their availability

MODERN VIEW Nutrients can directly regulate
metabolism in a hormonal independent manner
CLASSICAL VIEW metabolic adaptations are
controlled only by hormonal or neuronal signals
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Regulation of fat/cell interactions
Lipids control the expression of genes involved
in their own metabolism
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PPARs are Nuclear receptors
NUCLEAR RECEPTOR LIGAND
Thyroid hormone R Thyroid hormone
Glucocorticoid R Cortisol
Estrogen R Estrogen
Progesterone R Progesterone
Androgen R Testosterone
PPAR Lipids

• Receptors found within the nucleus
• Bind directly to DNA and regulate gene expression
• Ligand activated transcription factors

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PPARPeroxisome Proliferator-Activated Receptors

• Nuclear receptors involved in the transcriptional
  regulation of lipid metabolism and energy balance
• Fatty acids and their derivatives (Acyl-CoA
  eicosanoids) are the natural ligands of PPAR

ANIMATION
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3 PPAR isotypes act as Fat Sensors
Any changes in endogenous fatty acid profiles
modulate the activity of PPAR
PPAR?
Fat Storage
PPARa
PPARd
Fat Catabolism
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PPARs modulate Fat Energy Metabolism
PPARa
PPAR?
PPARd
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PPAR a

• Acts in liver to maintain hepatic lipid
  homeostasis and reduces fat concentrations

Up-regulates genes involved in all aspects of Fat
Catabolism
NEFA Uptake
Peroxisomal ß-oxidation
NEFA Transport
Mitochondrial ß-oxidation
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BURNING LIVER FAT
Adipose Tissue
PPARa Activator
? epinephrine
NEB
HSL
? Insulin
Lipolisis
CO2
Liver
CO2
Muscles Udder
ß-oxidation
KB
KREBS
TG
CO2
NEFA
CO2
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Hepatic ?-oxidation is vital during NEB
Glucose demand vs. splanchnic supply
Glycerol
LIPOLISIS
GLUCONEOGENESIS
Cows are in a state of
continuous gluconeogenesis due to the rumen
degradation of carbohydrate to VFA
NEFA
ENERGY
ß-oxidation
TGs provide the gluconeogenesis pathway with
glycerol, reducing equivalents and ATP
Glucose from digestible energy intake (largely
from ruminal propionate) is less than demand by
500 g/d The discrepancy must be made up by
increased gluconeogenesis from amino acids,
lactate, and glycerol
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PPAR-a activators Fibrates

• fenofibrate, gemfibrozil
• used to lower triglycerides and raise HDL-C in
  dyslipidemia to reduce risk of cardiovascular
  events

• 2-phenoxy-2-methyl-propionic acid
• Hepagen
• used to treat fatty liver, related metabolic
  disorders and improve energy balance

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HEPAGEN
2-methyl-2-phenoxy-propionic acid 2-methyl-2-phen
oxy-propanoic acid 2-Phenoxyisobutyric
acid 2,2-Dimethylphenoxyacetic acid Mefepronic
acid
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CLINICAL TRIALS

• Effects of PPARa activation in dairy cows

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Effects of Hepagen on liver function and fertility

• 40 Holstein cows (2-5 lactation)

50 ml/cow
50 ml/cow
50 ml/cow
1 d
15 d
30 d
Calving
3 d
5 d
Biopsy
Biopsy
Biopsy

• Treated group 50 ml of Hepagen I.M. at calving,
  3d postpartum and 5d postpartum
• Control group 50 ml of physiological solution
  (NaCl 0.9)/ head at calving, 3d postpartum and
  5d postpartum

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Liver fat in control and Hepagen treated cows
1 d
15 d
30 d
CONTROL
TREATED
P lt 0.001
30 µm
Liver sections stained with toluidine blue
Sciorsci 2009
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Liver glycogen in control and Hepagen treated cows
1 d
15 d
30 d
CONTROL
TREATED
30 µm
Liver sections stained with haematoxylin-PAS to
highlight the presence of glycogen (purple).
Sciorsci 2009
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Albumins Protein Synthesis

• Albumin concentration significantly higher in
  the treated group
• Albumin concentration in the control group
  slightly lower than the normal range

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Reproductive Parameters
HEPAGEN
CONTROL
Sciorsci 2009
plt0.05
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Hepagen Effects on Ketosis

• 36 Holstein cows (2- 4 lactation)

50 ml/cow
50 ml/cow
50 ml/cow
Calving
10 d
-6/10 d
30 d
40 d
BHB
BHB
BHB
BHB
Bouda et al. 2008
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Hepagen Effects on Ketosis
plt0.05
Open days lower in Control than in Treated group
109.9 vs. 118.5 days
Bouda et al. 2008
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Hepagen Effects on Ketosis

• 57 Pluriparous Holstein cows

50 ml/cow
50 ml/cow
Calving
2 hours
-7/10 d
10 d
21 d
-5/8 d
2 d
BHB
BHB
BHB
BHB
BHB
CONTROL BCS 3.25 3.75 TREATED BCS 3.25 3.75
CONTROL BCS 4 TREATED BCS 4
Aparicio et al. 2009
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Serum BHB Concentrations
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Use Of Hepagen in the Transition Dairy Cow
Practical Experiences

• 200 Parmigiano-Reggiano cows

50 ml/cow
50 ml/cow
-20 d
Calving
Follow Up (postpartum diseases, fertility)
BHB once/week
Gorrieri 2009
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Use Of Hepagen in the Transition Dairy Cow
Practical Experiences
metritis, displaced abomasum
Gorrieri 2009
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HEPAGEN

• Preventive and Therapeutic Protocols for the
  Transition Cow

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Preventive protocols in close-up dry cows
To complement transition cow management programs
and herd preventive health care programs
Reduce risk of postpartum diseases

• Monitor and record for diseases occurring during
  the early lactation period in the herd
• Lactational incidence risk (LIR) affected /
  of calvings (at risk) in the same time period
• Case de?nitions/Con?dence of diagnosis grade
• Define targets for acceptable levels of incidence

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Preventive protocols in close-up dry cows
50 ml/cow
50 ml/cow
7-10 days before expected time of Calving
Day of calving
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Preventive Protocols in Fresh Cows
Identify primary target for prevention

• Cows at a higher risk of fatty liver and
  metabolic disordes
• Over-conditioned
• Underfed
• Quick weight loss
• Calving difficulties, Twins
• Predisposing diseases (Infections, RP, etc.)

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Preventive Protocols in Fresh Cows
50 ml/cow
50 ml/cow
Calving
After 2-3 days
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Therapeutic Protocols in Fresh cows
Best with Fresh Cow Medicine Programs
Daily Monitoring of Each Cow for First 10 Days
after Calving (Temperature and Physical
Exam) Early Identification and Treatment of
Problem Cows
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Diagnosis of Fatty Liver

• Difficult
• No specific symptoms
• Diagnosed by biopsy
• invasive technique
• hemorrhage, infection, death
• New promising ultrasound technology

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Diagnosis of Fatty Liver

• Cows having problems from the beginning of
  lactation
• Rapid weight and BCS loss, reduced feed intake
• Presence of ther diseases
• Diseases more severe and less responsive
• Milk fever cows that relapse and become downers
• Ketotic cows that dont respond to treatment
• Chronic mastitis cows
• Repeat breeders that defy all treatments
• Cows that relapse or go from one disease to
  another
• Reduced milk production
• Cows that are frequently culled

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Therapeutic Protocols in Fresh cows
50 ml/cow
50 ml/cow
Follow up and repeat where appropriate
Early Identify and Treat
After 24 h
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