Hepatic lipid metabolism

Because of its involvement with many aspects of lipid metabolism so far described, it will be apparent from the discussion so far that acetyl-CoA is an axle around which hepatic lipid metabolism revolves. Indeed, acetyl-CoA links lipid and carbohydrate metabolism. Figure 6.20 summarizes the central role of acetyl-CoA in lipid related pathways in the liver. 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

E. Elson. Influence of minor plant con-stituents on porcine hepatic lipid metabolism. Atherosclerosis 1987 HV104... 

Several studies have evaluated the effects of oral di(2-ethylhexyl) adipate on various aspects of hepatic lipid metabolism. Feeding di(2-ethylhexyl) adipate (2% of diet) to male Wistar rats for seven days resulted in increased hepatic fatty acid-binding protein as well as in increased microsomal stearoyl-CoA desaturation activity (Kawashima et al., 1983a,b). Feeding the compound at this dose for 14 days resulted in increased levels of hepatic phospholipids and a decline in phosphatidyl-choline phosphatidylethanolamine ratio (Yanagita et al., 1987). Feeding di(2-ethyl-hexyl) adipate (2% of diet) to male NZB mice for five days resulted in induction of fatty acid translocase, fatty acid transporter protein and fatty acid binding protein in the liver (Motojima et al., 1998). 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

Qureshi, A.A., Din, Z.Z., Abuirameileh, N., Burger, W.C., Ahmed, Y., and Elson, C.E. 1983. Suppression of avian hepatic lipid metabolism by solvent extracts of garlic impact on serum lipids. J. Nutr. 113, 1746-1755. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

Michael MD, Kulkami RN, Postic C et al. (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6 87-97 Neumann-Haefelin C, Beha A, Kuhlmann J et al. (2004) Muscle-type specific intramyocellular and hepatic lipid metabolism during starvation in Wistar rats. Diabetes 53 528-534... 

Martini RM. 1987. Acute effects of carbon disulfide on hepatic lipid metabolism in Fischer rats. Acta Cient Venez 38 362-365. 

Nonogaki, K., Pan, X.M., Moser, A.H., Shigenaga, J., Staprans, I., Sakamoto, N., Grunfeld, C., Feingold, K.R.. 1996. LIF and CNTF, which share the gpl30 transduction system, stimulate hepatic lipid metabolism in rats. Am. J. Physiol. 271 (3), E52I-E528, Pt. 1. 

Trauner, M. (2007) A little orphan runs to fat the orphan receptor small heterodimer partner as a key player in the regulation of hepatic lipid metabolism. Hepatology 46, 1-5. 

HPMC modulates plasma lipoprotein profiles and hepatic lipid levels. HPMC is not absorbed by the body, but its presence in the intestinal lumen increases fecal fat, sterol, and bile acid excretion, which results indirectly in changes in hepatic lipid metabolism. In recent studies of hepatic gene... 

Asiedu, D.K., Demoz, A., Skorve, J., Grav, H.J. Berge, R.K. (1995) Biochem. Pharmacol., 49, 1013-1022. Acute modulation of rat hepatic lipid metabolism by sulphur-substituted fatty acid analogues. 

Bochenek, W., and Rodgers, J. B., 1978, Effects of saturated and unsaturated fats given with and without dietary cholesterol on hepatic cholesterol synthesis and hepatic lipid metabolism, Biochim. Biophys. Acta 528 1. 

Lipoprotein alterations with niacin are thought to be due to changes in hepatic lipid metabolism and are not dependent on GPR109A. 

Skrede, S., Bremer, J., Berge, R.K. Rustan, A.C. (1994) J. Lipid Res., 35, 1395 1404. Stimulation of fatty acid oxidation hy a 3-thia fatty acid reduces triacylglycerol secretion in cultured rat hepatocytes. Asiedu, D.K., Demoz, A., Skorve, J., Grav, H.J. Berge, R.K. (1995) Biochem. Pharmacol., 49, 1013-1022. Acute modulation of rat hepatic lipid metabolism by sulphur-substituted fatty acid analogues. 

De Beer, M., R.W. Rosebrough, B.A. Russell, S.M. Poch, M.P. Richards, and C.N. Coon, 2007. An examination of the role of feeding regimens in reglating metabolism during the broiler breeder grower period. 1. Hepatic lipid metabolism. Poult. Sci. 86, 1726-1738. 

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