THE ACTIVITY OF THE METABOLIC FORM OF HEPATIC PHOSPHATIDATE PHOSPHOHYDROLASE CORRELATES WITH THE SEVERITY OF ALCOHOLIC FATTY LIVER IN HUMAN-BEINGS

Increased esterification of fatty acids to triglyceride is common to m ost of the mechanisms proposed to explain the causation of alcoholic f atty liver. However, it is unclear whether this is caused by increased substrate supply or whether direct stimulation of the enzymes of the esterification pathway occurs after excessive alcohol intake. The rate -limiting step in triglyceride synthesis is catalyzed by the enzyme ph osphatidate phosphohydrolase, which is present in the cytosol and micr osomes and is sensitive to inhibition by N-ethylmaleimide. This enzyme is physically distinct from a second form of phosphatidate phosphohyd rolase that is located predominantly in the plasma membrane, is insens itive to N-ethylmaleimide inhibition and has a putative role in cell-s ignaling. We have investigated whether the activity of the N-ethylmale imide-sensitive (''metabolic'') form of phosphatidate phosphohydrolase is increased in patients with alcoholic liver disease and whether any increased activity correlates with the severity of steatosis. N-ethyl maleimide-sensitive and -insensitive phosphatidate phosphohydrolase ac tivities were measured in needle liver biopsy specimens from 42 alcoho lic patients and 6 patients with primary biliary cirrhosis and in wedg e biopsy specimens from 6 normal patients undergoing routine cholecyst ectomy. Steatosis was ''scored'' on coded slides from 0 to 3. N-ethylm aleimide-sensitive activity was higher in alcoholic biopsy specimens s coring 3 (3.25 +/- 0.4 units/mg protein, n = 10) than in those scoring either 0 (1.21 +/- 0.2, n = 14) or 1 to 2 (1.58 +/- 0.2, n = 18), and it was also higher than in biopsy specimens from normal and primary b iliary cirrhosis patients (1.65 +/- 0.3, n = 12; p < 0.0001, analysis of variance). No differences were found in age, weight, cumulative or current alcohol intake, coexistent cirrhosis or N-ethylmaleimide-insen sitive activity between the groups of alcoholic patients with differen t fat scores. These results demonstrate that the activity of metabolic , N-ethylmaleimide-sensitive phosphatidate phosphohydrolase is increas ed in some patients with alcoholic liver disease. That this increase w as only observed in patients with severe alcoholic steatosis suggests that the activity of this enzyme may play a role in the pathogenesis o f alcoholic fatty liver and may, in part, explain differences in susce ptibility to this common complication of alcohol abuse.