1. Volume 56, Issue 4, Pages 952-964 (April 2012)
The interaction of hepatic lipid and glucose metabolism in liver diseases 
Lars P. Bechmann, Rebekka A. Hannivoort, Guido Gerken, Gökhan S. Hotamisligil, Michael Trauner, Ali Canbay 
Journal of Hepatology 
Volume 56, Issue 4, Pages (April 2012)
DOI: /j.jhep
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

2. Fig. 1
Hepatic lipid metabolism in health and disease. (A) Dietary lipids are emulsified in the intestinal tract by bile acids (BAs). Hydrolyzed lipids are absorbed by enterocytes and packed into nascent chylomicrons (NCs). NCs enter the bloodstream via the thoracic duct where they receive important apoproteins (apoE; apoC-II) from HDL. These apoproteins are important for chylomicrons (C) to deliver TAGs and FAs to adipocytes and myocytes via lipoprotein lipase (LPL) degradation. Chylomicron remnants are taken up by hepatocytes via LDL-receptor (LDLR) and LDL receptor-related protein (LRP)-mediated endocytosis. BA synthesis is regulated by LRH1 and FXR, which activate BA export pumps. BA re-uptake by enterocytes stimulates FGF-19 release into the portal blood, which inhibits BA synthesis. (B) Free fatty acids (FFA) derive from lipolysis in adipose tissue and are actively taken up by various FA transporters under the control of insulin (Ins) and nuclear receptor signaling. Under physiologic conditions, the bulk of FAs is oxidized intramitochondrially and provides ATP and acetyl-CoA for the tricarboxylic acid cycle (TCA). Triglycerides (TAGs) derived from de novo lipogenesis are either stored in lipid droplets (LD) or packed into VLDL and exported into the blood stream. Acetyl-CoA for de novo lipogenesis is provided by the pyruvate dehydrogenase complex (PDC), which catalyzes oxidation of pyruvate, the end product of glycolysis. (C) Under physiologic conditions, β-oxidation of short-, medium- and long-chain FAs (SCFA, MCFA, LCFA) are degraded in mitochondria. Therefore, FAs are activated to acyl-CoA and shuttled across the mitochondrial membrane by carnitine palmitoyltransferase-1 (CPT1). Malonyl-CoA, an intermediate of lipogenesis, inhibits CPT1 and thus FA oxidation in the mitochondria. With FA abundance and in the insulin resistant state, LCFA and very-long-chain FAs (VLCFA) are oxidized in peroxisomes and the ER. This leads to an abundance of metabolites that induce formation of ROS and contribute to lipotoxicity. (D) In NASH, increased peripheral lipolysis, upregulation of FA transporters, an increase in DNL, and a switch from mitochondrial β-oxidation to peroxisomal and ω-oxidation promote FA toxicity and the release of ROS. This leads to the induction of hepatocyte apoptosis, the invasion and activation of inflammatory cells, as well as fibrogenesis.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

3. Fig. 2
Regulation of hepatic glucose metabolism. (A) After intestinal absorption, glucose (Glu) reaches the hepatocyte via the portal vein. The insulin-independent glucose transporter 2 (GLUT2) shuttles Glu across the membrane. Abundance of glucose induces conformational changes of the glucokinase regulatory protein (GCKR), which binds to glucokinase (GCK) and keeps it in the nucleus in the fasting state. GCK is then released into the cytosol and phosphorylates Glu to glucose-6-phosphate (Glu-6-P); depending on the nutritional state, it serves as a substrate for glycolysis or glycogen synthesis, respectively. GCK is transcriptionally regulated by insulin and nuclear receptor signaling. (B) Glu-6-P is a central intermediate in the hepatic glucose metabolism. It is degraded during glycolysis, which provides energy in the form of two ATP and two NADH molecules per glucose molecule. The product pyruvate is further decarboxylized to acetyl-CoA, which enters the intramitochondrial tricarboxylic acid cycle (TCA). Alternatively, Glu-6-P is degraded in the pentose-phosphate shunt, which provides NADPH, a co-substrate for DNL. Acetyl-CoA is an important product of the TCA, linking glucose and lipid metabolism, as it is the substrate for DNL (Fig. 1). Gluconeogenesis and glycogenolysis provide Glu-6-P as a substrate for glucose synthesis in the fasting state. Glucogenolysis is catalyzed by glycogen phosphorylase, activated by AMP, and repressed by insulin. The key enzyme in gluconeogenesis is PEPCK, which is repressed by insulin signaling via Akt-mediated FoxO phosphorylation and activated by PPARα.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

4. Fig. 3
Hepatic lipid and glucose metabolism in HCC. (A) Mediators of NAFLD progression also contribute to carcinogenesis in the liver. In general, obesity and diabetes have been identified as risk factors for cancer development as well as inflammation. Cirrhosis is a precancerous condition and, in fact, most HCCs derive from cirrhotic livers. Important mediators of insulin resistance and lipotoxicity also induce dysplasia and carcinogenesis. This figure gives a brief overview of different cytokines and cell signaling pathways involved in HCC development. (B) Expression of GLUT1 in hepatoma cells leads to increased hepatic glucose utilization. Glucokinase is downregulated, but hexokinase 2 (HK2) is now expressed and phosphorylates glucose with a higher affinity. Aerobic glycolysis leads to a rapid, but rather ineffective energy supply to the proliferating cancer cell. However, this process, referred to as the Warburg effect, facilitates uptake and de novo synthesis of nutrients (nucleotides, amino acids, lipids), available for cell proliferation and tumor growth. (C) Clinically, this effect is utilized in PET diagnostics. An increase in cancer cell glucose uptake, as visualized by FDG PET/CT, acts as an important tool in HCC diagnostics.
Journal of Hepatology  , DOI: ( /j.jhep )
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

5. Journal of Hepatology 2012 56, 952-964DOI: (10. 1016/j. jhep. 2011. 08
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

6. Journal of Hepatology 2012 56, 952-964DOI: (10. 1016/j. jhep. 2011. 08
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions

7. Journal of Hepatology 2012 56, 952-964DOI: (10. 1016/j. jhep. 2011. 08
Copyright © 2012 European Association for the Study of the Liver Terms and Conditions