Hepatocyte Heterogeneity in the Metabolism of Fatty Acids: Discrepancies on Zonation of Acetyl-CoA Carboxylase

Abstract

Lipid metabolism appears to be less zonated than carbohydrate and protein metabolism. Studies on the zonation of lipid metabolism have been centered in particular on fatty acid synthesis which, according to the concept of metabolic zonation, should be a predominantly perivenous process while fatty acid oxidation should be periportal. There are, however, conflicting data on the activity gradients of lipogenic enzymes as well as measurements of actual synthesis of fatty acid and very low density lipoprotein. Data obtained by microdissection show a 1.5- to 2-fold higher activity of acetyl-CoA carboxylase and citrate lyase in the perivenous zone in agreement with measurements of the actual rate of fatty acid synthesis in preparations of hepatocyte, enriched in periportal or perivenous cells. On the other hand, results obtained with the dual-digitonin-pulse perfusion technique demonstrate the opposite gradient in the form of a 2- to 3-fold higher specific activity of acetyl-CoA carboxylase in the periportal zone based on measurements of the acetyl-CoA carboxylase protein proper. This specific activity gradient, which applies to male and not female rats, disappears almost completely in the fasted-refed animal, were lipogenesis is strongly induced. In this review we attempt to rationalize these discrepancies in the results as methodological differences which in particular apply to the following parameters: (1) expression of results (reference substance); (2) selectivity of zonal sampling, and (3) differences in methodology of acetyl-CoA carboxylase measurements. It is concluded that these factors could account for the discrepancies, but further studies, in particular on the zonation acetyl- CoA carboxylase mRNA, are required in order to further understand the zonation of lipid metabolism and its possible role in the metabolic regulation of the liver.

Metabolic zonation of the liver: The oxygen gradient revisited

“…Further, complementing pathways can be linked, and substrate demanding activities can be carried out at sites with the best substrate provison. Although not all metabolic activities need to be zonated, metabolic zonation has been shown for carbohydrate, amino acid, lipid, ammonia, and xenobiotic metabolisms (covered in many excellent reviews [7], [8], [9], [10], [11], [12], [13] (Fig. 1C)).…”

Zonation of metabolism and gene expression in liver

“…The zonal heterogeneity of the liver has been reviewed recently both in general (Jungermann and Katz 1989;Gumucio 1989a, b;Quistorff 1990;Katz and Jungermann 1992) and in particular with focus on the metabolism of carbohydrates (Jungermann and Thurman 1992), lipids (Bass 1989;Quistorff et al 1992), amino acids and ammonia (Hfiussinger etal. 1992), xenobiotics Traber 1989), bile acids (Groothuis and Meijer 1992) and plasma proteins (Feldmann et al 1992) as well as the diverse functions of the various non-parenchymal cells (Bouwens et al 1992).…”

Differential Intrahepatic Phospholipid Zonation in Simple Steatosis and Nonalcoholic Steatohepatitis

“…Most in situ information on the metabolic zonation of lipids comes from gene expression measurements of proteins regulating lipid metabolism such as acetyl-coA carboxylase [6], β-hydroxy-butyryl-CoA dehydrogenase [7], 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase [8], and carnitine palmitoyltransferase I [6], [9]. Lipogenesis, inferred by increased acetyl-CoA carboxylase mass and activity measurements, occurs primarily in periportal (zone 1) hepatocytes [10]. Fatty acid oxidation, on the other hand, has been reported to occur preferentially in perivenular (zone 3) zones as suggested by the mildly increased expression of phosphatidate phosphatase and apolipoprotein C2 [6], [11], [12].…”