Lecture 20 - Ketogenesis & Fatty Acid Synthesis Notes

Instructor: J. Scott Pattison, Ph.D.
Date: March 17, 2025
Location: Lee Med Bldg, Room 111
Contact: james.pattison@usd.edu

Synthesis of Ketone Bodies in Liver: Identify the process and location of ketone body synthesis and their utilization by extrahepatic tissues.
Conditions Favoring Synthesis: Understand conditions that promote ketogenesis in the liver and how ketone bodies are utilized by non-liver tissues.

Comparison of Fatty Acid Synthesis vs. Oxidation: Examine differences in cellular location, key redox coenzymes, reaction sequences, and regulatory mechanisms.
Role of Citrate: Explain how citrate affects lipid synthesis.
Sources of NADPH: Identify various sources of NADPH essential for fatty acid synthesis.
Hormonal Regulation: Discuss hormonal influences on fatty acid synthesis and oxidation.

Carnitine Acyl Transferase-1 (CAT-1): Malonyl CoA, a byproduct of fatty acid synthesis, inhibits CAT-1, preventing fatty acids from entering the mitochondrial matrix where β-oxidation occurs.

Primary Site: Ketogenesis mainly occurs in liver mitochondria when Acetyl CoA accumulates due to excess fatty acid flow from adipose tissue or glucogenic substrate limitation.
Pathway Details: Ketone bodies (Acetoacetate, β-Hydroxybutyrate, and Acetone) are formed when Acetyl CoA levels are elevated. Acetoacetate and β-Hydroxybutyrate can be utilized as energy sources in muscle tissues.

Formation Trigger: Increased Acetyl CoA levels above TCA cycle capacity leads to ketogenesis, particularly during low glucose availability. Elevated fatty acids or depleted glycogen stores induce the process.
Enzyme Involvement: Lack of the enzyme Succinyl-CoA transferase in the liver means it cannot utilize ketone bodies for energy, unlike other tissues.

Metabolism of Ketone Bodies: Ketone bodies are oxidized in mitochondria of non-liver tissues, converting them to Acetyl CoA for TCA cycle entry, generating ATP.

Pathological Conditions: In diabetic ketoacidosis, low insulin levels lead to elevated glucagon and cortisol, stimulating excessive ketone body synthesis.
Clinical Examples: Diabetic patients often present with ketoacidosis due to glucose deficiency, characterized by high levels of ketone bodies, dehydration, and altered blood pH, which can result in coma or death.

High Glucose Conditions: Under high glucose, insulin promotes fatty acid biosynthesis through Acetyl CoA conversion to citrate, occurring primarily in liver and adipose tissue cytosol.

Acetyl CoA Carboxylase (ACC): The key enzyme controlling fatty acid synthesis; catalyzes the formation of Malonyl CoA from Acetyl CoA.
Hormonal Regulation of ACC: AMPK inhibits ACC during low energy states, while insulin activates it through dephosphorylation.
Malonyl CoA Role: Serves as a substrate for fatty acid synthase and inhibits CAT-1.

Citrate Shuttle: Excess citrate exported from mitochondria serves as a substrate for fatty acid synthesis.
NADPH Sources: Mainly derived from the Pentose Phosphate Pathway; also generated by malic enzyme.

Parameter	Synthesis	Oxidation
Cellular Location	Cytoplasm	Mitochondrial matrix
Redox Coenzyme	NADPH (reduction)	FAD, NAD+ (oxidation)
Rate Limiting Step	Acetyl-CoA → Malonyl CoA	Transport across mitochondrial inner membrane (CAT-1 inhibited by Malonyl-CoA)
Acetyl-CoA Source	From Citrate	From Fatty Acids

End Products: FA synthesis leads to the production of Palmitate, primarily occurring in the liver during high glucose conditions.
Feedback Inhibition: Palmitoyl CoA inhibits ACC, controlling fatty acid synthesis.
Essential Fatty Acids: Linoleic acid must be sourced from diet as humans cannot add double bonds beyond C-9.
Intermediate Pathways: Triglycerides synthesized from glycerol 3-phosphate and fatty acyl-CoA derivatives form phosphatidic acid, essential for fat metabolism.