The effects of cortisol, corticotropin and thyroxine on the synthesis of glycerolipids and on the phosphatidate phosphohydrolase activity in rat liver

Abstract

1. Male rats were injected daily for 5 days with 0.15m-NaCl, corticotropin, cortisol or l-thyroxine and the rates of glycerolipid synthesis were measured in the livers after intraportal injection of [(14)C]palmitate and [(3)H]glycerol. 2. Injection of all three hormones decreased the rates of body-weight gain. 3. Cortisol treatment increased the weight of the liver relative to body weight. 4. Thyroxine treatment increased the relative rate of triacylglycerol synthesis from [(3)H]glycerol and decreased the relative accumulation of (3)H and (14)C in diacylglycerol. It did not significantly alter the accumulation of these isotopes in phosphatidate nor the activity of the soluble phosphatidate phosphohydrolase in the total liver. However, this activity increased by 1.5-fold when expressed relative to the soluble protein of the liver. The increased triacylglycerol synthesis appears to be related to a general increase in the turnover of fatty acids in the liver. 5. Treatment with cortisol and corticotropin increased the relative rate of triacylglycerol synthesis from [(3)H]glycerol, decreased the accumulation of (3)H in phosphatidate and increased the flux of both isotopes from phosphatidate to diacylglycerol. This appeared to be caused by the increased activity of the soluble phosphatidate phosphohydrolase that was observed in the livers of the cortisol-treated rats. 6. It is proposed that cortisol could be directly or indirectly involved in increasing the activity of hepatic phosphatidate phosphohydrolase in starvation, diabetes, laparotomy, subtotal hepatectomy, liver damage, ethanol feeding and in obesity. This enzyme adaptation could contribute to the potential of the liver to increase its synthesis and accumulation of triacylglycerols or to secrete very-low-density lipoproteins.

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…Not unexpectedly, the RSG-induced insulin reduction was modest and nonsignificant in insulinsensitive, chow-fed control rats; however, RSG was able to negate the rise in insulin brought about by chronically high levels of CORT. With regard to lipid accumulation in oxidative tissues, as expected because of its well-established lipogenic 52,53 and fatty acid oxidation-reducing action, 54 the robust increase in local CORT concentration in the liver achieved under HiCORT conditions resulted in a marked increase in liver TG content. Treatment with RSG not only decreased liver TG in vehicle-implanted rats but also abrogated HiCORT-induced steatosis.…”

Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically

“…However, the accumulation of TAG in the liver could also be lipotoxic (43). We now show that lipin-1 specifically is responsible for the GC-induced increase in PAP1 activity, which we previously showed to result in increased hepatic glycerolipid synthesis (7). As FA concentrations increase and exceed the capacity for b-oxidation, PAP1 translocates to ER membranes to facilitate the storage of the excess FA as TAG in fat droplets, resulting in steatosis (5).…”

“…By contrast, PAP1 appears to be specific for PA as a substrate (3,4) and is a required enzyme in the biosynthesis of triacylglycerol (TAG), phosphatidylcholine, and phosphatidylethanolamine (5). Our previous work showed that injecting rats with cortisol or corticotropin produced marked increases in PAP1 activity in the liver (6,7). Subsequent work with rat hepatocytes demonstrated that the glucocorticoid (GC) effect in increasing PAP1 activity was synergized by glucagon and inhibited by insulin (8,9).…”

Glucocorticoids and non-alcoholic fatty liver disease

“…In combination with a high fat diet, GC excess was associated with increased fibrosis although interestingly the inflammatory response was relatively suppressed (46). GCs increase lipid biosynthesis within the liver that can lead to hepatic steatosis as well as increasing circulating TAG levels (47,48). Multiple mechanisms are believed to be important including, increased hepatic Diaglyceride Acyltransferase (DGAT) expression (37) and enhanced free fatty acid delivery into the portal circulation.…”