L92 Abnormalities or Dynamics of Lipid Metabolism

Sterols

Cholesterol cholesterol esters, bile acids, steroid hormones

Function of sterols

Cell membranes(phospholipids & cholesterol)

Hormones (cortisol, sex hormones, Vit D)

Bile acids

Lipids found in animals

Mono / di / Triglycerides, (TG)

Glycerol esters: Fatty acids (FA), Sphingosenes

Terpenes: vitamins A, E, & K.

Function of lipids found in animals

TG & FA - Energy source

Lipoproteins =

lipid (Triglyceride or Cholesterol) + protein (apoproteins) - (HDL, LDL, VLDL, LDLs)

• Transport in body without forming large lipid masses

When lipids are absorbed from the diet:

(20-30%) are esterified in enterocytes (gut cells) & cannot travel as such in blood

Cholesterol packaged into lipoproteins (LDL and HDL) are

released into lymph → transported into bloodstream

Triglycerides (TG) are stored in?

adipose tissue or packaged into chylomicrons (dietary) and VLDL (hepatic) for transport

Lipoproteins percentages: usually measure fractions in man (not vet spp)

Ingested (Exogenous) Cholesterol Metabolism (high insulin)

1. Ingestion (approx. 20-30%) → Absorbed in SI or from liver synthesis (biliary secretion) → Bile salts aggregate → micelles in SI

3. → hydrolyzed by pancreatic & intestinal lipase enzymes in gut lumen → absorbed into intestinal cells - free cholesterol re-esterified with fatty acids

5. free cholesterol and cholesteryl esters are secreted into chylomicron particles (remnants)

Ingested (Exogenous)Triglyceride (TG) Metabolism(High Insulin)

TG hydrolyzed in intestinal lumen by pancreatic lipase → mono & diglycerides, free fatty acids (FFA) → combine with phospholipid & bile salts → form micelles

→ absorbed into intestinal cells → re-esterified to form TG

4. TGs + cholesteryl esters, free cholesterol, phospholipid, & proteins incorporated into chylomicron particles → circulation via the lymphatics

Cholesterol Synthesis If fasted, then (70-80%) Synthesized - Endogenous

Chylomicron, VLDL, LDL & Liver Cholesterol Metabolism

Endogenous (Fasted) Triglyceride (TG) Metabolism

Summary Points

TGs transported via chylomicrons (dietary), VLDL(hepatic)

LPL (lipoprotein lipase) is key to TG clearance;(enhanced by insulin) - ↑ uptake of FFAs from chylomicrons / VLDL into adipose tissue

Insulin promotes TG (fat) formation & storage in adipose tissue

HSL Hormone sensitive lipase intracellular enzyme in lipocytes

In fasted state (↓ insulin) HSL hydrolyzes stored triglycerides into free fatty acids (FFA) + glycerol (lipolysis) → mobilization of stored TG → hypertriglyceridemia

High TGs can trigger or worsen pancreatitis, especially in predisposed breeds (eg Miniature Schnauzer)

Lipemia (Lipidemia)

describe turbid (cloudy) appearance(chylomicrons & VLDLs – high TG)

• Presence of lipids in serum /plasma,

Often incorrectly used to describe an concentration of circulating lipids

What does lipemia effect?

Can affect serum chemistries (method dependent)

• ↑ Bile acids, Calcium

• ↓ Na, Cl

• Can also affect Liver , pancreatic enzymes bilirubin, glucose

Hyperlipidemia /Hyperlipemia

abnormal ↑ lipids in serum /plasma(post 12 hr fast)

Cause turbidity of sample (high triglycerides)

Hyperlipidemia occurs after ingesting a meal

Fasting hyperlipidemia →

abnormal lipid metabolism / endocrine disease

Hyperlipoproteinemia =

↑Lipid proteins (LP)(triglyceride &/or cholesterol) + protein

Hyperlipidemia does not always result in?

lipemia(only presence of chylomicrons or VLDL – high in triglycerides)

Hypercholesterolemia =

↑ LDL & HDL – does not cause lipemia of sample

Hypertriglyceridemia (TG) tube examples

Chylomicrons = Exogenous lipemia due to dietary fat(usually post prandial)

VLDL’s = Endogenous lipemia produced in liver by endogenous triglycerides

Classification Hyperlipemia/Hyperlipoproteinemia/Hyperlipidemia: Physiologic(postprandial)

Dogs & cats: ↑chylomicrons

• Expect clearing < 8 hr(< 16 hr – seems long)

• If delayed clearing, think secondary (acquired) hyperlipidemia

Classification Hyperlipemia / Hyperlipoproteinemia/Hyperlipidemia: primary

congenital; hereditary

• certain breeds – Min Schnauzers

Classification Hyperlipemia / Hyperlipoproteinemia/Hyperlipidemia: secondary(more common)

acquired: especially if not eating or associated with endocrine or metabolic disorders

• Pancreatitis, cholestasis, PLN, obesity, High fat diets, drugs

Physiologic Hyperlipidemia

Postprandial (ingest TGs) in small animals, ↑ Formation chylomicrons, ↑ TG (& Cholesterol)

• May persist for 16 hours if fatty meal

Always try to fast patient for 8 hours before collecting blood(not in very small / debilitated animals / exotics)

Physiologic hyperlipidemia results in?

lipemia - can interfere with analytes (esp. bile acids)

Primary / Idiopathic Hyperlipidemia

Familial in Miniature Schnauzers → Inherited defect in lipoprotein lipase(defective lipolysis of lipoproteins - intravascular) or apoprotein CII enzymes

• Usually > 4 years old

Primary/idiopathic hyperlipidemia results in?

High triglycerides & hyperchylomicronemia

• ± Mild hypercholesterolemia

Chronic hyperlipidemia can result in ↑ ALP, abdominal pain, predispose to pancreatitis and seizures

Primary/idiopathic hyperlipidemia can also be seen in?

occasionally Beagles, Poodles, Shelties

Primary/idiopathic hyperlipidemia in cats

Type III LPL def. in cats

• Himalayan, Siamese, DSH(autosomal recessive)

Primary/Idiopathic Hyperlipidemia: Clinical signs - Dogs

V/D/ pancreatitis, ± diabetes

Seizures - synthesis of myelin and other essential fatty portions of the CNS, resulting in conduction disturbances and seizures

• (Neuro Sx -usually Triglycerides > 1000 mg/dL)

Primary Hyperlipidemia – Cats clinical signs(young cats 8-9 mos)

Multiple hematomas affect peripheral nerves, causing loss of sensation

• Facial / limb /pharyngeal paralysis

• Horner's syndrome

Muscle atrophy, Cutaneous xanthomas - lipid-laden macrophages in the skin

Triglycerides > 1500 mg/dL (RI< 100-150 mg/dL), lipemia retinalis or lipemia acqueous

• Also hypercholesterolemia

Primary Hyperlipidemia Inherited (Familial): Hypercholesterolemia

Idiopathic: unknown defect in Doberman pinschers, Rottweilers & Briards

• Cholesterol ↑↑↑ triglycerides ↑

• Animals are often asymptomatic

Secondary Hyperlipidemia: Endocrine causes

• Hypothyroidism

• Diabetes mellitus

• Hyperadrenocorticism (Cushing’s)

Secondary hyperlipidemia: endocrine lab signs

↓ LPL (Lipoprotein lipase) activity → ↓ clearance of LDL

↓ lipolysis of VLDL

↑ cholesterol / ↑ triglycerides

Secondary hyperlipidemia: metabolic

Pancreatits (Acute)

• Hepatic Disease

• Nephrotic Syndrome

• Obesity

• Equine / Camelid hyperlipidemia (triglycerides)

Hypothyroidism ↓ T4: Low thyroid ↓ LPL

↓ Cholesterol uptake/ slow lipid metabolism

↓ T3 ↓ hepatic lipase degradation of cholesterol to bile acids

Serum cholesterol can be markedly increased ↑↑ in ± 80% of dogs (LDL)

Also mild ↑ TG

May result in vascular disease and subsequent neurologic or cardiac abnormalities

Diabetes Mellitus: ↓ Insulin

↓ LPL activity, ↓ Clearing chylomicrons and VLDL

↑ Hormone-sensitive lipase (HPL) activity → ↑ lipolysis → more free fatty acids FFA → ↑ VLDL production by liver (influx of FA)

Liver re-esterifies FA to TG → VLDL, Converts FFAs to ketones → Hyperlipoproteinemia, ↑ ↑ ↑ Triglyceride & ↑ cholesterol

• Can predispose to pancreatitis

Hyperadrenocorticism(Cushing’s disease): Steroids

↑ Cholesterol (common) & ↑ triglyceride

↑ Lipolysis (↑ free FA from TG + glycerol breakdown), ↑ Synthesis of VLDL (& LDL) by the liver, ↑ Hormone-sensitive lipase (HSL) ↑ FA influx

Steroids antagonize insulin → peripheral insulin resistance → ↓ LPL activity (slower removal / clearance of lipoproteins)

Acute Pancreatitis: ↑ Triglycerides & / or ↑ cholesterol

Cytokines & stress (cortisol) stim lipolysis → ↓ LPL activity

• ?↓Insulin ↓ LPL activity - ↑ VLDLs

Can be due to cholestasis or DM } pathogenesis unknown

Prolonged hypertriglyceridemia may predispose to pancreatitis

Cholestatic Hepatic disease

↑ Cholesterol / triglycerides seen with cholestatic disease(Liver is major route of cholesterol excretion)

Nephrotic syndrome - Protein Losing Glomerulonephropathy: Hypercholesterolemia ↑↑

↓ Lipolysis of lipoproteins with Apoprotein B → ↓ Intravascular processing(loss of protein needed for LPL binding?)

• Stimulate VLDL synthesis in hepatocytes, ↑ TG

Hypoalbuminemia

• Proteinuria, Edema or ascites

Hepatic Lipidosis – due to Negative Energy Balance seen in?

Lactating dairy cows

Pregnancy toxemia sheep / goats (twin lambs)

Anorexic obese cats, small equids & camelids

Hepatic Lipidosis & Ketosis in Cows (Especially Dairy Cows)

Negative energy balance in early lactation (first 2–6 weeks postpartum) but late lactation can develop clinical ketosis

High-producing cows can’t eat enough to meet the massive energy demand for milk production = pregnancy ketosis

Hepatic lipidosis and ketosis in dairy cows: metabolic pathway

1. Low glucose → low insulin → ↑ glucagon & catecholamines ↑ HSL activity → fat mobilization -

Adipose tissue releases NEFAs (Non-Esterified Fatty acids) into blood →Liver takes up NEFAs: Some oxidized for energy, Some converted into ketone bodies(acetoacetate → β-hydroxybutyrate, acetone).

• Some are re-esterified into triglycerides, but: Cattle have limited ability to export VLDL, so TG accumulate in the liver → fatty liver, but ketosis common

Bovine Ketosis Bloodwork and Diagnostics:

↑ NEFAs Test for negative energy balance Non esterified fatty acids (pre-calving)

↑ Ketones (especially β-hydroxybutyrate, aka BHB) – Usually post calving

• ↓ Glucose

• AST ↑ if hepatocellular injury from lipidosis

Ketosis Sheep Pregnancy toxemia

Late gestation, when ewes carrying multiple fetuses cannot meet their energy demands → Decreased glucose leads to negative energy balance → Fat mobilization, and ketone buildup - clinical ketosis

Clinical signs of ketosis sheep pregnancy toxemia

Dehydration, Weight loss, decreased milk yield, Weakness

Grinding teeth (pain sign), Sweet/acetone odor on breath or urine, Ruminal stasis and constipation

CNS signs : sometimes apparent blindness

• Trembling, muscle twitching

• Aimless wandering, head pressing, star-gazing, convulsions, coma

Feline Hepatic Lipidosis (& Ketosis):

Often secondary to anorexia, especially in obese cats

Triggers: stress, illness, change in diet, etc

Feline hepatic lipidosis and ketosis: metabolic pathway

Anorexia → low insulin → ↑ HSL (hormone sens lipase)activity → fat mobilization

Fat (NEFAs (non-esterified fatty acids)) floods the liver → limited capacity for hepatic β-oxidation of fatty acids → liver re-esterifies them into TGs

bad at exporting those triglycerides as VLDL → Excess fat accumulates as hepatic triglycerides → hepatic lipidosis→ impairs liver function

Can develop secondary ketosis

Results in accumulation of free (unesterified) cholesterol in plasma

Equine Hyperlipidemia: Mild problem, TG < 500 mg/dL

During fasting liver re-esterifies NEFAs into TGs → exports them into blood as VLDL → VLDL particles accumulate in blood → Hyperlipidemia and organ damage

• In ponies/donkeys, LPL is reduced

Common diseases associated with hyperlipidemia in horses are:

PPID- Pars pituitary intermedia dysfunction(hyperglycemia, insulin resistance, and hirsutism)

Colic, Laminitis, GI parasites

Equine Hyperlipidemic Syndrome: Severe Hypertriglyceridemia ↑ ↑ TG > 500 mg/dL

Seen in small equids(Miniature horses, ponies, donkeys)

During systemic disease that produces a negative energy balance - starvation or chronic illness, obesity, pregnancy, lactation, stress, and transportation, enterocolitis, parasitism, gastric impaction or colic

Also ↑ cholesterol

Equine Hyperlipidemic Syndrome: Severe Hypertriglyceridemia ↑ ↑ TG > 500 mg/dL metabolic pathway

Horses have poorly developed pathways for ketone production(Cannot convert mobilized fatty acids to ketones)

↑ VLDL production → Hypoglycemia, ± Hyperlipidemia → Hepatic lipidosis → Eventually liver failure → Renal disease and CNS signs

• Fatal in more than 60% of cases

Hyperlipemia in Camelids

Males and females can develop hepatic lipidosis and ketosis in negative energy balance(Stress, anorexia, pregnancy, lactation)

Females often in late pregnancy (pregnancy toxemia) or early lactation

Hyperlipidemia due to ↑ triglycerides [mostly VLDL], cholesterol and ketosis

• Can die due to hepatic lipidosis

Hypolipidemia causes

Liver Failure

Chronic liver diseases (e.g. cirrhosis)

Portosystemic shunts

Hypolipidemia results in?

↓ Production - ↓ cholesterol, ↓ TG, ↓ Apoproteins, ↓ phospholipids, ↓ VLDLs, ↓ plasma lipoproteins

Hypocholesterolemia / hypotriglyceridemia

• May also see low urea, albumin, glucose

Hypolipidemia due to GI / pancreatic disease

Maldigestion (exocrine pancreatic insufficiency - EPI)

• Malabsorption

• Protein losing enteropathy

• Lymphangiectasia

• Starvation