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After studying this chapter, you should be able to:

  • Describe the processes by which fatty acids are transported in the blood and activated and transported into the matrix of the mitochondria for breakdown to obtain energy.

  • Outline the β-oxidation pathway by which fatty acids are metabolized to acetyl-CoA and explain how this leads to the production of large quantities of ATP from the reducing equivalents produced during β-oxidation and further metabolism of the acetyl-CoA via the citric acid cycle.

  • Identify the three compounds termed “ketone bodies” and describe the reactions by which they are formed in liver mitochondria.

  • Appreciate that ketone bodies are important fuels for extrahepatic tissues and indicate the conditions in which their synthesis and use are favored.

  • Indicate the three stages in the metabolism of fatty acids where ketogenesis is regulated.

  • Understand that overproduction of ketone bodies leads to ketosis and, if prolonged, ketoacidosis, and identify pathological conditions when this occurs.

  • Give examples of diseases associated with impaired fatty acid oxidation.


Although fatty acids are broken down by oxidation to acetyl-CoA and also synthesized from acetyl-CoA, fatty acid oxidation is not the simple reverse of fatty acid biosynthesis but an entirely different process taking place in a separate compartment of the cell. The separation of fatty acid oxidation in mitochondria from biosynthesis in the cytosol allows each process to be individually controlled and integrated with tissue requirements. Each step in fatty acid oxidation involves acyl-CoA derivatives, is catalyzed by separate enzymes, utilizes NAD+ and FAD as coenzymes, and generates ATP. It is an aerobic process, requiring the presence of oxygen.

Increased fatty acid oxidation is a characteristic of starvation and of diabetes mellitus, and leads to increased ketone body production by the liver (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, for example, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, for example, hypoglycin.


Fatty Acids Are Transported in the Blood as Free Fatty Acids

Free fatty acids (FFAs)—also called unesterified (UFA) or nonesterified (NEFA) fatty acids (Chapter 21)—are fatty acids that are in the unesterified state. In plasma, longer chain FFA are combined with albumin, and in the cell they are attached to a fatty acid binding protein, so that in fact they are never really “free.” Shorter chain fatty acids are more water-soluble and exist as the unionized acid or as a fatty acid anion.

Fatty Acids Are Activated Before Being Catabolized


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