Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis

Abstract

The liver is an important site for iron and lipid metabolism and the main site for the interactions between these two metabolic pathways. Although conflicting results have been obtained, most studies support the hypothesis that iron plays a role in hepatic lipogenesis. Iron is an integral part of some enzymes and transporters involved in lipid metabolism and, as such, may exert a direct effect on hepatic lipid load, intrahepatic metabolic pathways and hepatic lipid secretion. On the other hand, iron in its ferrous form may indirectly affect lipid metabolism through its ability to induce oxidative stress and inflammation, a hypothesis which is currently the focus of much research in the field of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The present review will first discuss how iron might directly interact with the metabolism of hepatic lipids and then consider a new perspective on the way in which iron may have a role in the two hit hypothesis for the progression of NAFLD via ferroportin and the iron regulatory molecule hepcidin. The review concludes that iron has important interactions with lipid metabolism in the liver that can impact on the development of NAFLD/NASH. More defined studies are required to improve our understanding of these effects.

Keywords: Hepcidin; Iron; Lipids; Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis; Oxidative stress.

Figure 1

Possible sites (shown in bold) of interactions between iron and lipid metabolism. Iron deficiency can have its effects by generating anaemia/hypoxia while iron overload can interact by generating oxidative stress/lipid peroxidation and cytokine production. The grey area shows the basolateral surface of the hepatocyte bathed in the sinusoidal fluid. The green area is the canalicular surface through which bile is actively secreted into the biliary canaliculi. The orange area shows the lipoproteins and enzymes acting in peripheral circulation. CM: Chylomicron; CMR: Chylomicron remnant; VLDL: Very low density lipoprotein; IDL: Intermediate density lipoprotein; LDL: Low density lipoprotein; HDL: High density lipoprotein; LDLR: LDL (apo B/E) receptor; LRP: LDL receptor related protein; FABP: Fatty acid binding protein; FAT/CD36: Fatty acid translocase; SR-B1: Scavenger receptor-B1; NEFA: Non-esterified fatty acid; CE: Cholesteryl ester; SFA: Saturated fatty acid; MUFA: Mono-unsaturated fatty acid; TG: Triglycerides; apo-B: Apolipoprotein-B; DNL: de novo lipogenesis; LD: Lipid droplet; LPL: Lipoprotein lipase; HL: Hepatic lipase; LCAT: Lecithin cholesterol acyltransferase; GPAT: Glycerol-3-phosphate acyltransferase; DGAT: Diacylglycerol acyltransferase; SCD: Steroyl CoA desaturase; FAS: Fatty acid synthase; HMG CoA R: HMG CoA reductase; 7αOHase: 7α hydroxylase; ACAT: Acyl-CoA cholesterol acyltransferase; MTP: Mitochondrial Trifunctional protein; ADRP: Adipose differentiation-related protein.

Figure 2

Schematic diagram depicting disease progression in non-alcoholic fatty liver disease modified after Gentile and Pagliassotti[101]. Iron overload is generally hypothesised to play a role in generation of second hit. In non-alcoholic fatty liver (NAFL) disease, iron overload in the liver may promote the development and progression of steatohepatitis, working in a feed-forward manner to promote the “third hit”, on-going injury and death of hepatocytes leading to fibrosis and cirrhosis. NASH: Non-alcoholic steatohepatitis.