Control of Metabolic Diseases in Dairy Cows

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Control of Metabolic Diseases in Dairy Cows

• Roberto Farina DVM Fatro Group

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High incidence of Metabolic Diseases
Control of Metabolic Diseases is crucially
important for modern dairy herds

• Intensive feeding and management
• Susceptibility of high yielding cows

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• Metabolism
• All the chemical and physical changes that take
  place within the body and enable its growth and
  functioning

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Regulation of Metabolism

• The coordination of body tissue metabolism
  involves two types of regulation
• Homeostasis
• Homeorhesis

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Homeostasis - Resistance to change

• Maintenance of physiological equilibrium
• This control operates to maintain constant
  conditions within the internal environment
• The property of returning to the state a system
  was in before it was disturbed

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Homeorhesis - Maintaining the flow

• Coordinated changes in metabolism to adapt to a
  new physiological state

• One example of this is the dairy cow transition
  period where a series of coordinated changes
  occur to support a successful lactation

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The Transition Period

• The last 3 wk before to 3 wk after parturition
  (Grummer 1995)

Pregnant Nonlactating
Nonpregnant Lactating
Extreme CHALLENGE

• Most infectious and metabolic diseases in dairy
  cows occur during or soon after this time

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Negative Energy Balance (NEB)
Adapted from Bell by Drackley 1999
4 day postpartum

• After parturition extra energy requirement for
  milk production is not met by feed energy intake

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DRY MATTER INTAKE (DMI) AROUND CALVING
Bertice 1992
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Glucose demand vs. supply during the
periparturient period
Overton 1998 Douglas 1998
After calving glucose supply is less than demand
by 500 g/d
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Centrality of the Liver
Gluconeogenesis Glycogenesis Glycogenolysis Syn
thesis of Lipoprotein Synthesis
of Cholesterol Synthesis of Phospholipids Deamin
ation of Aminoacids Transamination reactions
Synthesis of Urea Synthesis of Amino
Acids Synthesis of Albumin Synthesis of
Clotting Factors Synthesis of Fibrinolytic
Factors Oxidation of Fatty Acids Ketogenesis Bi
le production Metabolism of Hormones
Metabolism of Vitamins Detoxification of
Xenobiotics Detoxification of Drugs Detoxificati
on of end-metabolism products
Liver is at the crossroads of metabolism

• Its rapid adaptation to support lactation is
  central for an uneventful transition

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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
Liver Metabolic Activity 4.4 mmol O2/g 8.6 mmol O2/g X 2
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The greatest challenges to the liver during the
transition period
High energy requirements
Extensive NEFA Mobilization
Dramatic increase in metabolic activity
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Effective Means to Control Metabolic Diseases in
Dairy Cows

• L-Carnitine and its manifold advantages in
  treating metabolic disorders
• Peroxisomal Proliferators
• Ways to detoxify ammonia
• Oxidative stress control

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FATTY LIVER

• Burning off liver fat

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Fat mobilization syndrome
Vacuoles in hepatocytes of a liver showing
steatosis

• Cows mobilize fatty acids from adipose tissue to
  compensate for energy deficit

• TGs accumulate in liver of almost all
  high-producing cows during the first few weeks
  postpartum
• Fatty liver is a common condition (up to
  50 of HP dairy cows)

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Lipid Metabolism During the Transition Period
Peroxisomes

• Insulin

Adipose Tissue
TG
Fatty Liver
Stress Hormones
NEFA
NEFA
Liver
TG
CPT
Mitochondria
BETA-OXIDATION
VLDL
CO2
Ketone Bodies
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Serum NEFA concentration around calving
NEFA mM/L
Weeks relative to calving
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Serum NEFA concentration around calving
Underwood 1998
NEFA concentration mEq/L
Days from parturition
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Changes in the concentration of hepatic TGs in
relation to the day of calving
Liver TG - DM basis
Day relative to calving
Vazquez-Anon 1994
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Hepatic lipid accumulation

• Impairs liver function
• Synthesis and biotrasformation of metabolites
• Detoxification and excretion of toxic waste
  products and xenobiotics

Detrimental effects on health status, well-being,
productivity and reproductive performance of
dairy cows
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Hepatic lipid accumulation

• Decreased feed intake
• Poor reproductive performance
• Decreased milk production
• Impairment of immunity

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Fatty liver

• Associated with increased metabolic and
  infectious diseases
• Ketosis
• Displaced abomasum
• Milk fever
• Downer cow syndrome
• Infertility
• Mastitis
• Endometritis

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Effects of NEFA on IgM secretion in PBMC
N. Lacetera 2004
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Effects of NEFA on interferon-? secretion in PBMC
N. Lacetera 2004
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High NEFA and fatty liver are associated 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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Control of hepatic lipidosis
Stimulating peroxisomal ß-oxidation
Peroxisomes

• Insulin

Reducing NEFA mobilization
Adipose Tissue
TG
Fatty Liver
Stress Hormones
NEFA
NEFA
Liver
TG
Boosting VLDL synthesis
CPT
Mitochondria
BETA-OXIDATION
VLDL
Stimulating mitochondrial ß-oxidation
CO2
Ketone Bodies
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Activation of mitochondrial ß-oxidation

• Low rate of synthesis and export of VLDL in
  ruminants liver
• Oxidation is the most important means of
  depleting excess fatty acid from ruminant liver

L-CARNITINE
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Inner Mitochondrial Membrane is Impermeable to FA
Carnitine
Carnitine transports FA inside the mitochondria
where they are burnt to produce energy
(ß-oxidation)
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The Carnitine Shuffle
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Activation of Peroxisomal ß-oxidation

• Pathway to oxidize FA during extensive NEFA
  mobilization

• It is induced by dietary fat, starvation,
  uncontrolled diabetes, and some compounds

PEROXISOMAL PROLIFERATORS
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HEPAGEN
Active substance
Phenoxy-2-methyl-2 propionic acid
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HEPAGEN

• Hepagen acts by binding PPARa (Peroxisome
  Proliferator Activated Receptor alpha)
• A nuclear receptor belonging to the PPAR family
• Receptors that play a central role in
  coordinating energy balance

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Peroxisome proliferator activated receptors
(PPARs)

• 3 main isotypes
• PPARa, PPARd (or ß), PPAR?
• Transcription factors
• Once activated, PPARs bind to DNA and regulate
  gene transcription
• The ligands for the PPARs are free fatty acids
  and eicosanoids

Genes
Enzymes
Metabolism 
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HEPAGEN Mechanism of action
Activated by Hepagen PPARa interacts with RXR and
then , binding to specific response
elements (PPREs), regulates the expression of
target genes involved in the catabolism of fatty
acids
RXR Retinoid X Receptor
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PPARa

• A central regulator of hepatic lipid metabolism
• Control of fatty acid transport and uptake
• Activation of long-chain fatty acid into acyl-CoA
  (acyl-CoA synthetase)
• Enzymes involved in the ß-oxidation pathway
• Metabolism of lipoproteins

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HEPAGEN
The only specific antisteatotic drug available in
veterinary medicine

• Stimulates peroxisomal and mitochondrial
  ß-oxidation
• Promotes FA catabolism
• Reduces hepatic synthesis of TGs
• Raises HDL Cholesterol (Important for
  steroidogenesis and fertility)

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HEPAGEN
Stimulation of hepatic regenerative capacity
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Ammonia Intoxication

• Boosting liver detoxifying capacity

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Ammonia Intoxication

• Fatty Liver
• Acidosis
• Ketosis
• Intoxications
• Infectious diseases

• Rations low in digestible energy
• High non-protein nitrogen feeding (Urea)
• Excessive or highly degradable protein in the
  diet

Decreased liver detoxifying capacity
Gluconeogenesis from aminoacids
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Hepatic triglyceride accumulation reduces
ureagenic capacity up to 40
Strang 1998
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Peripartum Ammonia Intoxication

• Ammonia in peripheral blood doubles when liver
  triglyceride concentrations increased during the
  postpartum (Zhu 2000)
• Early lactation cows also consume more total and
  ruminally degradable protein than do prepartum
  cows

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Ammonia toxicity

• Affects intermediary metabolism
• Decreases the ability of hepatocytes to
  synthesize glucose
• Increases the incidence of metabolic disorders
• Reduces milk production
• Affects eggs and embryos and impairs reproductive
  performance

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Ammonia strongly inhibits liver capacity to
synthesize glucose
(Overton 1999)
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METABOLASEDetoxifying action on ammonia

• L-Ornithine
• L-Citrulline
• L-Arginine
• Aspartic acid
• Glutamic acid
• L-Carnitine

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Hepatic detoxification of ammonia
AMMONIA
Aspartic acid
Citrulline
UREA CYCLE
Arginine
Ornithine
UREA
Ureogenesis takes place in the liver and is
essential for ammonia detoxification
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Extrahepatic detoxification of ammonia
GLUTAMIC ACID AMMONIA
ASPARTIC ACID AMMONIA
GLUTAMINE
ASPARAGINE
AMMONIA
RENAL SECRETION
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AMMONIA
Ornithine
Citrulline
Aspartic acid
UREA CYCLE
Glutamic acid
Asparagine Glutamine
Arginine
UREA
AMMONIA
URINE
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I.V. Carnitine prevents hyperammoniemia in
ruminants
Changes in plasma ammonia N in sheep following
i.v. L-carnitine administration and oral urea
load test
AMMONIA µmol/L
Control
Carnitine
Time, minutes
Chapa 1998
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Oxydative Stress

• The last challange

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ROS AND FREE RADICALS
Reactive Oxygen Species are intermediate products
in oxidative metabolism
OXIDATIVE STRESS

• Conditions when ROS are generated faster than
  they can be safely neutralized by antioxidant
  mechanisms

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ROS sources

• Continually produced in cells and removed by the
  antioxidant defense systems
• Energy production in mitochondria
• Many enzymatic reactions
• Detoxification processes
• Immune response

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ROS Toxicity

• High predisposition to interact with other
  molecules
• Cause notable damage to cells and tissues
• ROS are deleterious under so-called oxidative
  stress conditions
• Inflammations, infections
• Environmental stress
• High Producing Dairy Cows

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Oxydative Stress And Metabolic Diseases

• Close correlation between oxidative status and
  recovery from metabolic diseases
• ROS affects
• Mitochondrial function
• Immune system
• Tissue perfusion
• Enzyme activity
• DNA
• Membrane lipids

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METABOLASEAntioxidant activity

• L-Carnitine
• Lipoic Acid
• Glycine

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Arachidonic acid and oxidative stress
Membrane Phospholipids

• Arachidonic acid plays an important role in
  inflammation
• Arachidonic acid plays an important role in the
  formation of oxygen free radicals via stimulation
  of NADPH oxidase System

PL
NADPH Oxidase
PG LT
Oxidative stress
Inflammation
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Carnitine inhibits arachidonic acid turnover and
oxidative stress
Membrane Phospholipids
Carnitine reduces Arachidonic acid availability
(Pignatelli 2003)
PL
AA
CARNITINE
NADPH Oxidase
ß-OXIDATION
PG LT
ß-OXIDATION
Oxidative stress
Inflammation
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LIPOIC or THIOCTIC ACID
Passing from the disulfhydryl to the disulphide
form and vice-versa, it is an efficient
oxidation-reduction system
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LIPOIC/THIOCTIC ACID The Ideal
Antioxidant

• Unique in its ability to act as an antioxidant
  both in fat and water
• It scavanges most reactive oxygen species
• It is capable of regenerating vitamin C, vitamin
  E and glutathione
• It has a metal chelating activity

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Glycine

• Glycine, a simple nonessential amino acid, is a
  well-known inhibitory neurotransmitter, that acts
  via a glycine-gated chloride channel
• Also Kupffer cells and other macrophages express
  a glycine-gated chloride channel
• The inhibitory effect of glycine on these cells
  reduces ROS and cytokines production

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The antisteatotic role of Peroxisomal
Proliferators
Specific regulator of Lipid Metabolism Promotes
Fatty acids catabolism Reduces hepatic fatty
infiltration Fights fatty liver and related
metabolic disorders
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When to treat

• Metabolase Hepagen

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Indications

• Preventive treatments in close-up dry cows
• Periparturient disorders (Milk Fever, Ketosis,
  Displaced Abomasus, Retained Fetal Membranes,
  Mastitis)
• Fresh Cow Medicine Programs

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Thank You

• These slides are available on Metabolase website
  at www.metabolase.com