Synthesis of Fatty Acids and Triacylglycerols

These flashcards cover key concepts related to the synthesis of fatty acids and triacylglycerols, including metabolic pathways, regulatory factors, and associated diseases.

Where does de novo fatty acid synthesis occur in eukaryotic cells?

In the cytosol.

Which tissues are primary sites for fatty acid synthesis?

Liver, adipose tissue, mammary glands.

Primary location for FA synthesis within cells?

The cytosol.

What is the initial precursor molecule for fatty acid synthesis?

Acetyl-CoA.

From what metabolic pathway is Acetyl-CoA primarily derived for FA synthesis?

Glucose metabolism.

How is mitochondrial Acetyl-CoA transported to the cytosol for FA synthesis?

Via the citrate shuttle.

What enzyme cleaves cytosolic citrate to regenerate Acetyl-CoA?

ATP-citrate lyase.

What molecule is regenerated along with Acetyl-CoA from citrate cleavage?

Oxaloacetate.

What are the two major cytosolic sources of NADPH for fatty acid synthesis?

Pentose phosphate pathway and malic enzyme reaction.

How does malic enzyme contribute to NADPH production for FA synthesis?

By converting malate to pyruvate.

NADPH provides what kind of power for fatty acid synthesis?

Reducing power.

What enzyme catalyzes the rate-limiting step of fatty acid synthesis?

Acetyl-CoA carboxylase (ACC).

What is the rate-limiting and committed step in fatty acid synthesis?

The carboxylation of Acetyl-CoA to Malonyl-CoA.

What essential cofactor is required by ACC, functioning as a prosthetic group?

Biotin.

What energy molecule is consumed by ACC during Malonyl-CoA formation?

ATP.

Malonyl-CoA is what kind of carbon unit for elongation via FAS?

A three-carbon unit.

What allosterically activates Acetyl-CoA carboxylase (ACC)?

Citrate.

What hormone stimulates ACC?

Insulin.

How does insulin activate ACC?

Promotes its dephosphorylation.

What allosterically inhibits ACC, signaling sufficient fatty acid levels?

Long-chain fatty acyl-CoAs.

What hormones inhibit ACC by promoting its phosphorylation via cAMP-dependent protein kinase?

Glucagon and epinephrine.

Citrate promotes ACC activity when which molecules are abundant?

Acetyl-CoA and ATP.

Inhibition of ACC reduces the synthesis of what molecule?

Malonyl-CoA.

What is the description of human fatty acid synthase (FAS)?

A large, multi-functional enzyme complex.

What is the final product of fatty acid synthesis catalyzed by FAS in humans?

Palmitate (a 16-carbon saturated fatty acid).

What three main substrates are required for FAS elongation cycles?

Acetyl-CoA (priming), Malonyl-CoA (elongation), NADPH (reductions).

What prosthetic group on FAS acts as a carrier for the growing acyl chain?

Acyl carrier protein (ACP).

What is embedded in ACP to carry acyl groups?

Phosphopantetheine group.

What is the initial priming step in FAS?

Transfer of Acetyl group to cysteine and ACP.

What are the four core enzymatic reactions of one FAS elongation cycle?

Condensation, Ketone Reduction, Dehydration, Enoyl Reduction.

In FAS condensation, what molecule condenses with the growing acyl chain?

Malonyl group (on ACP).

What byproduct is released during the condensation step of FAS?

CO2.

Specific role of NADPH in FAS elongation?

Provides reducing power for two reduction steps.

How many NADPH molecules consumed per 2-carbon unit added by FAS?

Two.

How many cycles of FAS are needed to synthesize palmitate?

Seven cycles.

How is palmitate released from FAS?

By a thioesterase enzyme.

What is the stoichiometry to make one palmitate?

1 Acetyl-CoA, 7 Malonyl-CoA, 14 NADPH.

What is the main energetic cost beyond NADPH and ACC-ATP?

1 ATP per Malonyl-CoA formed.

Where do fatty acid elongation systems primarily act to produce longer chains (>16C)?

In the endoplasmic reticulum (ER).

What molecule is the 2-carbon unit donor for ER fatty acid elongation?

Malonyl-CoA.

What reducing agent is required for ER fatty acid elongation?

NADPH.

How does ER elongation mechanism differ from FAS?

Uses separate enzymes for each step.

An example product of ER elongation from palmitate?

Stearate (18:0 from 16:0).

Where does fatty acid desaturation (introduction of double bonds) primarily occur?

In the endoplasmic reticulum (ER).

What enzymes are responsible for introducing double bonds into saturated fatty acids?

Desaturases (mixed-function oxidases).

What cofactor for desaturase donates electrons?

NADH (or NADPH).

What cofactor for desaturase is the ultimate electron acceptor?

Molecular oxygen (\text{O}_2).

What other protein is required for desaturases?

Cytochrome b_5.

Give an example of a desaturation reaction's product.

Oleic acid (18:1\Delta^9).

Desaturation of stearic acid (18:0) forms what?

Oleic acid (18:1\Delta^9).

What specific desaturase converts stearic to oleic acid?

\Delta^9-desaturase.

Position of the first double bond introduced by humans?

\Delta^9 position.

Which desaturase enzymes do humans possess?

\Delta^9, \Delta^6, \Delta^5, \Delta^4-desaturases.

Why are humans unable to synthesize double bonds beyond carbon 9?

They lack specific desaturase enzymes.

Define 'essential fatty acids'.

FAs the body cannot synthesize, obtained from diet.

Name the two primary essential fatty acids found in the diet.

Linoleic acid (omega-6) and alpha-linolenic acid (omega-3).

Linoleic acid classification?

Omega-6 fatty acid (18:2\Delta^{9,12}).

Alpha-linolenic acid classification?

Omega-3 fatty acid (18:3\Delta^{9,12,15}).

What important 20-carbon fatty acid is derived from dietary linoleic acid?

Arachidonic acid (20:4\Delta^{5,8,11,14}).

What processes are involved in converting linoleic acid to arachidonic acid?

Elongation and desaturation.

What important omega-3 fatty acids are derived from alpha-linolenic acid?

Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA).

What is the primary function of synthesizing triacylglycerols?

To store excess fatty acids as efficient energy reserve.

What are the two main locations for triacylglycerol synthesis in the body?

Liver and adipose tissue.

What is the three-carbon backbone molecule for triacylglycerol synthesis?

Glycerol 3-phosphate.

What is the first committed intermediate in the synthesis of both TAGs and glycerophospholipids?

Phosphatidic acid.

Describe the initial steps of TAG synthesis from glycerol 3-phosphate.

Two fatty acyl-CoAs are added, forming lysophosphatidic acid, then phosphatidic acid.

What enzyme removes the phosphate group from phosphatidic acid?

Phosphatidic acid phosphatase.

What is another name for phosphatidic acid phosphatase?

Lipin.

What is the final step in triacylglycerol synthesis?

Addition of a third fatty acyl-CoA by DGAT.

What enzyme adds the third fatty acyl-CoA to diacylglycerol?

Diacylglycerol acyltransferase (DGAT).

How is glycerol 3-phosphate primarily produced in the liver?

By phosphorylation of glycerol (glycerol kinase) or reduction of DHAP (glycolysis).

How is glycerol 3-phosphate primarily produced in adipose tissue?

Almost exclusively by reduction of dihydroxyacetone phosphate (DHAP) from glycolysis.

Why is glycerol kinase important in the liver for TAG synthesis?

Allows utilization of circulating glycerol.

Does adipose tissue have significant glycerol kinase activity?

No.

What hormone is crucial for G3P production in adipose tissue via glucose uptake?

Insulin.

In a fasting state, is TAG synthesis in adipose tissue impaired?

Yes, due to low DHAP.

What is the primary function of Very Low-Density Lipoproteins (VLDL)?

Transport endogenous triacylglycerols from liver to peripheral tissues.

What is the primary apolipoprotein found on VLDL particles?

Apolipoprotein B-100 (apoB-100).

Where are VLDL particles assembled and secreted?

In the liver (hepatocytes).

What is the primary function of chylomicrons?

Transport exogenous (dietary) triacylglycerols from intestine to peripheral tissues.

What is the primary apolipoprotein found on chylomicron particles?

Apolipoprotein B-48 (apoB-48).

Where are chylomicron particles assembled and secreted?

In intestinal mucosal cells (enterocytes).

What enzyme hydrolyzes triacylglycerols in capillaries from VLDL and chylomicrons?

Lipoprotein lipase (LPL).

What apolipoprotein activates Lipoprotein lipase (LPL)?

ApoC-II.

What is a consequence of lipoprotein lipase deficiency?

Build-up of chylomicrons and VLDL in blood (hypertriglyceridemia).

What condition occurs with LPL deficiency?

Hypertriglyceridemia.

What characterizes Alcoholic Fatty Liver Disease (AFLD)?

Fat (triacylglycerol) accumulation in liver cells due to excessive alcohol.

How does excessive alcohol consumption alter the hepatocellular NADH/NAD+ ratio?

Produces significant NADH, leading to elevated NADH/NAD+ ratio.

How does a high NADH/NAD+ ratio contribute to increased FA synthesis in AFLD?

Shifts equilibrium towards substrates like glycerol 3-phosphate for TAG synthesis.

How does a high NADH/NAD+ ratio inhibit fatty acid oxidation in AFLD?

Inhibits enzymes of the citric acid cycle and \beta-oxidation.

How does alcohol consumption impair VLDL secretion from the liver in AFLD?

Interferes with apoB-100 synthesis and VLDL assembly.

The overall impact of AFLD on the liver is?

Fat accumulation and impaired export.

What characterizes Non-Alcoholic Fatty Liver Disease (NAFLD)?

Fat accumulation in the liver not caused by excessive alcohol.

What are major risk factors for NAFLD?

Insulin resistance, obesity, type 2 diabetes, metabolic syndrome.

How does insulin resistance contribute to increased hepatic fat in NAFLD?

Increases adipose lipolysis (more FFA to liver) and hepatic de novo lipogenesis.

What is the more severe form of NAFLD, characterized by inflammation and liver cell damage?

Non-alcoholic steatohepatitis (NASH).

How do high glucose/fructose loads contribute to hepatic de novo lipogenesis in NAFLD?

Provide rapid substrates for increased fatty acid synthesis.

What is the effect of a MTTP (Microsomal Triglyceride Transfer Protein) mutation on NAFLD?

Can lead to decreased VLDL secretion, contributing to hepatic TAG.

Beyond insulin resistance, what else promotes elevated hepatic DNL in NAFLD?

High glucose/fructose consumption.

What is the impact of excessive fructose consumption on hepatic FA synthesis?

Leads to increased hepatic de novo lipogenesis.