Regulation of fat metabolism in the liver: link to non-alcoholic hepatic steatosis and impact of physical exercise

Abstract

Hepatic steatosis may develop as a consequence of several dysfunctions. An increased circulating non-esterified fatty acid (NEFA) pool seems to be a major determinant in the pathogenesis of non-alcoholic fatty liver disease. Increased activation of the transcription factor sterol-regulatory-element-binding protein-1c, which promotes fatty acid synthesis, also contributes to hepatic fat accumulation. Increased hepatic fat oxidation with hepatic steatosis may be triggered by increased hepatic fat concentrations through the action of hepatic peroxisomes mediated by peroxisome proliferator-activated receptor alpha. Finally, inhibition in very low density lipoprotein secretion may also result in hepatic steatosis. This appears to be mainly controlled by the esterification of NEFAs into triacylglycerols by diacyglycerol acyltransferase-1 and -2 and the microsomal transfer protein. Physical exercise would interfere with the development of hepatic steatosis by stimulating lipid oxidation and inhibiting lipid synthesis in liver through the activation of the AMP-activated protein kinase pathway.

Habitual Physical Activity Is Associated With Intrahepatic Fat Content in Humans

“…Taking into account the fact that excessive fatty liver accumulation appeared to be peculiarly associated with hepatic insulin resistance (5) and that reduction of the IHF content due to a moderate weight reduction was associated with improvement of hepatic insulin sensitivity (24), the potential beneficial effect of physical exercise would represent an additional tool to improve the metabolic profile of patients type 2 diabetes. The precise mechanisms by which physical exercise may reduce hepatic steatosis remains unknown and needs to be extensively explored, even if it was suggested that it would stimulate lipid oxidation and inhibit lipid synthesis in liver through the activation of the AMPactivated protein kinase pathway (25).…”

“…IHF content was assessed in a quantitative fashion and noninvasively as a continuous variable by means of 1 H magnetic resonance spectroscopy (MRS), and habitual physical activity was assessed by means of a questionnaire. Fatty liver was defined as IHF content of Ͼ5% wet weight, and insulin sensitivity was estimated using the computer homeostasis model assessment (HOMA)-2 indexes.RESULTS -A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25,11,25, and 2% in quartile 1, 2, 3, and 4, respectively; 2 ϭ 15.63; P ϭ 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson's r ϭ Ϫ0.27; P Ͻ 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r ϭ Ϫ0.25; P Ͻ 0.001).…”

“…RESULTS -A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25,11,25, and 2% in quartile 1, 2, 3, and 4, respectively; 2 ϭ 15.63; P ϭ 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson's r ϭ Ϫ0.27; P Ͻ 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r ϭ Ϫ0.25; P Ͻ 0.001).…”

Infusion of a Lipid Emulsion Modulates AMPK and Related Proteins in Rat Liver, Muscle, and Adipose Tissues

“…Decreased mitochondrial FA oxidation has long been considered as the primary mechanism underlying the disruptions in lipid metabolism in the liver leading to TG accumulation (36). Previously, reduced liver mRNA of PPARα and FA oxidizing enzymes, such as acyl-CoA oxidase, have been observed in several models of FA and/or insulin-resistant rodents (37).…”

“…This occurs in part through the inhibition of SREBP1c by suppressing its gene transcription, mRNA stabilization and proteolytic cleavage in the liver (16). Given that plasma lipid concentration is directly related to the influx of lipids to the liver (36), defects in lipid oxidative capacity therefore further aggravate fat accumulation. Thus, it seems logical that decreased lipid synthesis reflects a compensatory mechanism in order to prevent further lipid accumulation.…”