Systems II Hepatic Physiology 1 (Digestive Functions)

The liver is a _____ gatekeeper, connecting digestive absorption to systemic nutrient availability

metabolic

The liver allows _____, _____, _____, _____, and _____ of nutrients so that intestinal absorption does not directly determine systemic nutrient availability.

first-pass metabolism, storage, redistribution, elimination, regulation

Bile

an aqueous product produced and secreted by the liver

Bile is a solution of

bile salts, phospholipids, cholesterol, conjugated bilirubin, electrolytes, water

Bile salts are _____ causing lipid droplets to disperse into smaller

micelles

amphipathic

Functions of bile (3)

1. Facilitate emulsification of fats in the diet (to increase surface area for digestive enzymes)

2. Facilitate absorption of lipids and fat-soluble vitamins (as micelles)

3. Elimination of waste products (by adding them to the intestinal lumen)

Bile is produced by the

liver

Bile is secreted through the

common bile duct

Bile is secreted into the

small intestine (or for storage into the gallbladder)

Bile is continuously secreted by _____ into bile _____

hepatocytes, canaliculi

CYP7A1

Enzyme that synthesizes the first and rate-limiting step of bile acid synthesis

Canalicular bile is

isosmotic (flow is driven osmotically by active bile salt

secretion)

FGF19

feedback from reabsorption of bile acids in intestine that negatively regulates bile acid synthesis

Cholangiocytes

bile duct cells that dilute bile by secreting chloride and bicarbonate isosmotically

Bicarbonate helps to _____ stomach acid entering the intestine

buffer

Cholangiocytes are regulated by

[cAMP] (↑ secretin, glucagon, VIP; ↓ somatostatin)

The gall bladder tends to dilute bile by absorbing fluid (T/F)

False (isotonic reabsorption of NaCl & NaHCO3- concentrates bile)

Bile secreted into the small intestine is a mixture of the

dilute ductal bile and concentrated gallbladder bile

Bile flow into the intestine is regulated by (2 things)

1. the volume of bile produced (flow rate) and

2. relative tone of the gallbladder and the sphincter of Oddi

Flow rate of bile is regulated by (3 things)

1. Bile acid feedback: FXR-mediated inhibition of cholesterol 7α- hydroxylase

2. Secretin: stimulates ductal HCO3- secretion

3. Somatostatin: inhibits ductal HCO3 secretion

Relative tone of the gallbladder is regulated by (3 things)

1. CCK (fats in small intestine): gallbladder contraction & sphincter of Oddi relaxation

2. FGF19 (bile in small intestine): gallbladder relaxation

3. Vagal input (rest & digest): relaxes sphincter and contracts gallbladder

Bile enters the small intestine to facilitate

emulsifications of fats (for digestion)

Approximately 95% of bile acids secreted into the small intestine are

reabsorbed either _____ or _____

passively (acid neutralization), actively (enterocytes in ileum)

Bile acids in enterocytes stimulate the secretion of

FGF19

Does venous blood draining the gastrointestinal tract return directly to the heart?

No

Which vein does most GI venous blood enter? Which organ does it flow to first?

hepatic portal vein, liver

First-pass metabolic functions of the liver (3 things)

1. Modify nutrients

2. Store excess substrates

3. Detoxify or inactivate compounds

First-pass metabolism

pre-systemic processing of blood by the liver (before returning to the heart)

The liver stores excess glucose as

glycogen

The liver regulates circulating

amino acid levels

The liver repackages lipids for

systemic delivery

The liver acts as a buffer by doing what?

smoothing fluctuations in nutrient absorption (prevents rapid swings in blood glucose and nutrient availability)

How does the liver detoxify the blood?

Drugs, toxins, and gut-derived metabolites reach the liver first, where hepatocytes convert many into less toxic or more excretable forms

The liver aids the immune system by

protecting systemic circulation while promoting immune

tolerance (exposed to dietary antigens and microbial products)

The liver preferentially metabolizes what for energy?

aromatic amino acids

The liver only minimally metabolizes

branched-chain amino acids

Why can disruption of the AAA:BCAA ratio lead to neurotransmitter imbalance and neurological effects?

AAA and BCAA compete for the same transporter in the brain

The BCAA:AAA ratio can be used as a marker of what?

liver function (low if first-pass metabolism is not occurring)

Like nutrients, drugs absorbed from the gastrointestinal tract enter what vein?

hepatic portal vein

Does oral drug exposure always achieve the same effects as a systemically administered dose?

No (because it passes through the liver first)

Which three possible conditions would cause reduced or absent first-pass metabolism?

1. decreased functional hepatocyte mass

2. increased resistance to portal blood flow

3. increased portal blood bypassing the liver and entering

systemic circulation directly

_____-derived compounds reach systemic circulation unmodified

Gut (e.g. ammonia, AAA, drugs/toxins)

Common Clinical Manifestations of Liver Disease

Neurologic signs, altered drug responses, metabolic abnormalities, and failure to thrive or poor growth

What organ stabilizes blood glucose concentrations during feeding and fasting?

Liver

Hepatocytes buffer fluctuations in blood glucose by (two functions)

1. storing excess glucose as glycogen (in fed state)

2. producing glucose via glycogenolysis and gluconeogenesis (in fasting state)

How does hormonal regulation integrate digestion with hepatic glucose metabolism?

In the fed state, insulin increases glycogenesis, glycolysis, and hepatic glucose output.

In the fasted state, glucagon increases glycogenolysis, gluconeogenesis, and hepatic glucose release.

What is the physiological significance of the liver's role in glucose metabolism?

Prevents large postprandial glucose spikes, maintains glucose availability between meals, and protects glucose-dependent tissues

How does hormonal regulation integrate digestion with hepatic amino acid metabolism?

In the fed state, insulin increases AA uptake and protein synthesis, and decreases AA oxidation.

In the fasted state, glucagon increases AA catabolism, gluconeogenesis, and urea production.

What is the physiological significance of the liver's role in amino acid metabolism?

Prevents toxic accumulation of ammonia, maintains plasma amino acid balance, supports glucose production during fasting, preserves neurologic function, and links protein intake to renal nitrogen excretion

How does hormonal regulation integrate digestion with hepatic lipid metabolism?

In the fed state, insulin increases lipogenesis, triglyceride synthesis, and VLDLs, and decreases fatty acid oxidation.

In the fasted state, glucagon increases fatty acid oxidation and ketone body production, and decreases lipogenesis.

What is the physiological significance of the liver's role in lipid metabolism?

Prevents postprandial lipid overload, distributes dietary fat to peripheral tissues, provides alternative fuels during fasting (ketones), and protects glucose availability for obligate tissues (brain, RBCs)

The liver is the central regulator of _____ metabolism.

cholesterol

Hepatocytes regulate cholesterol by

synthesizing, distributing, retrieving, and eliminating it

What is the physiological significance of the liver's role in cholesterol metabolism?

Buffers fluctuations in dietary intake, maintains membrane and steroid hormone supply, couples lipid digestion and cholesterol disposal, and prevents toxic accumulation of cholesterol in tissues

Cholesterol is synthesized from what molecule? Using what enzyme?

Acetyl-CoA, HMG-CoA reductase

Cholesterol is packaged into _____ and remodeled to _____ for delivery.

VLDL, LDL

What protein is responsible for the uptake of LDL?

LDLR (low-density lipoprotein receptor)

What protein is responsible for the uptake of HDL?

SR-B1

Cholesterol is eliminated as

bile acid

The liver buffers _____-soluble vitamin availability during feeding and fasting.

fat

Specific role of the liver regarding vitamin A

Stored in hepatic stellate cells

Specific role of the liver regarding vitamin D

First hydroxylation step occurs in the liver

Specific role of the liver regarding vitamin E

Hepatic sorting and redistribution via lipoproteins

Specific role of the liver regarding vitamin K

Required for hepatic synthesis of clotting factors

What is the physiological significance of the liver's role in vitamin availability?

Buffers intermittent dietary intake, prevents acute deficiency during fasting, allows delayed onset of deficiency with malabsorption (and links lipid digestion to vitamin availability to systemic function)

The liver buffers essential _____ availability during feeding and fasting.

micronutrient (hepatocytes are a central checkpoint between absorption and circulation)

How do hepatocytes regulate micronutrients in the fed state?

Manage uptake of absorbed micronutrients from portal blood, store micronutrients (along with hepatic macrophages/Kupffer cells), and prevent toxic spikes

How do hepatocytes regulate micronutrients in the fasted state?

Manage controlled release into circulation bound to

transport proteins and maintain stable plasma levels (despite variable intake)

Specific role of the liver regarding iron (micronutrient)

stores, exports out of the cell, and regulates intestinal absorption & macrophage release

Iron is stored as

ferritin and hemosiderin (hemosiderin when excessive)

Iron is exported by what protein? Bound to what other protein?

ferroportin, transferrin

Specific role of the liver regarding copper (micronutrient)

Incorporates into ceruloplasmin in hepatocytes and excretes excess into bile

Specific role of the liver regarding Vitamin B12 (micronutrient)

Stores in large quantities, supports DNA synthesis and erythropoiesis, manages delayed deficiency onset