Abnormal Lipid and Glucose Metabolism in Obesity: Implications for Nonalcoholic Fatty Liver Disease  Samir Parekh, Frank A. Anania  Gastroenterology  Volume 132, Issue 6, Pages 2191-2207 (May 2007) DOI: 10.1053/j.gastro.2007.03.055 Copyright © 2007 AGA Institute Terms and Conditions

Figure 1 (A) Steatosis: the presence of triglyceride stores in hepatocytes indicated by arrows; (B) polymorphonuclear leukocyte (PMN) infiltration, which may lead to inflammation and steatohepatitis; (C) ongoing hepatocyte injury, ballooning, and loss of steatosis indicating significant damage; (D) the presence of pericellular and pericentral fibrosis indicate an aggressive steatohepatitis that is more likely to progress to cirrhosis. Original magnification, ×200. Figure part D printed with permission. Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Figure 2 The present histopathologic understanding of the spectrum of liver disease and that NASH is the most severe form of this spectrum. (Matteoni CA, Younossi, ZM, Marchesini G, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathologic severity. Gastroenterology 1999;116:1413–1419). As has been pointed out previously, the significance of the histologic lesions as categorized may predict clinical outcome (McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis. J Clin Gastroenterol 2006;40:S17–S29.) Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Figure 3 Insulin resistance is the foundation for the accumulation of FFA and triglyceride storage in hepatocytes, or steatosis. Type 2 diabetes is also a consequence of insulin resistance, but hyperlipidemia, obesity, and diabetes can result in insulin resistance. At present, the progression of steatosis, which in most mammals is benign, is not currently known. Approximately 3% of patients with a nonalcoholic fatty liver (NAFL) suffer progression to nonalcoholic steatohepatitis (NASH). An active area of translational research should focus on the natural history of the progression of NAFLD. Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Figure 4 The current 2-hit hypothesis invoked in the progression of NAFLD. Although the first hit is believed to be a consequence of insulin resistance and, hence, is a focus of this review, the second hit, which results from the accumulation of fatty acids and triglycerides, is not reviewed here. However, numerous recent reviews examine the potential for oxidative stress from steatotic hepatocytes leading to lipid peroxidation; impaired mitochondrial and peroxisomal oxidation of fatty acids; and release of cytokines, chemokines, and adipokines that in concert result in lobular inflammation, hepatocyte necrosis, and apoptosis and cell dropout. The end result is a severe necroinflammatory hepatitis (NASH) that can lead to significant fibrosis. Some patients will develop frank cirrhosis with insipient complications including portal hypertension, encephalopathy, and hepatocellular carcinoma. Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Figure 5 Systemic insulin resistance coupled with impaired insulin action in skeletal muscle, adipose tissue, and hepatocyte leads to high circulating FFA loads as a consequence of the inability of mammals to handle both carbohydrate and fat loading. Normal handling of FFAs would result in (1) increased glycogen storage, (2) reduced de novo lipogenesis (DNL), (3) increased hepatic export of very-low-density lipoprotein (VLDL), and (4) enhanced oxidation of FFAs. The persistence of high circulating levels of FFAs and persistent hyperglycemia result in a series of changes in hepatic FFA metabolism that ultimately leads to hepatic steatosis. Impaired skeletal muscle and adipose tissue handling of triglycerides result in increased circulating FFAs that are transported across hepatocyte membranes and ultimately are incorporated into triglycerides. DNL is also increased in the insulin-resistant state, whereas decreased β-oxidation of FFAs and impaired synthesis and secretion of apolipoprotein B (ApoB) reduces the secretion of triglycerides from the liver as VLDLs. The consequence is net storage of hepatocyte storage of triglycerides, or steatosis. Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Figure 6 Hepatic diacylglycerol (DAG) content is increased because of excess delivery of FFAs from circulation or increased de novo lipogenesis (DNL), all a consequence of systemic insulin resistance. Exacerbating this problem is impaired β-oxidation of FFAs, and, when all 3 are taken together, a vicious cycle of hepatic insulin resistance emerges; namely, that there is failure of phosphorylation of the insulin receptor that in turn fails to phosphorylate the insulin receptor substrate 2 (IRS-2). The pathophyisologic consequences of this results in decreased glycogen synthesis because GSK3 is not phosphorylated, and the failure to phosphorylate FOXO results in nuclear translocation, up-regulation of phosphoenolpyruvate carboxykinase (PEPCK), and export of glucose by the GLUT2 transporter, further aggravating systemic and hepatic insulin resistance. Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Figure 7 FFAs or hepatic steatosis have been cited to cause direct damage to hepatocytes in the absence of the so-called second hit in the paradigm of the current “2-hit” hypothesis to explain the pathogenesis of liver injury in NAFLD. This synopsis slide demonstrates that FFAs can (1) induce endoplasmic reticular stress, or the unfolded protein response (UPR), and induce mitochondrial apoptosis; (2) FFAs can directly induce hepatocyte apoptosis and stimulate production of the adipocytokine tumor necrosis factor α (TNF-α); (3) FFAs have been shown to increase FAS ligand binding to the hepatocyte FAS receptor leading to extramitochondrial apoptosis; and (4) FFAs can result in impaired mitochondrial or peroxisomal β-oxidation of hepatocyte FFA stores that ultimately leads to production of hydrogen peroxide and other lipid peroxidation products that result in both apoptotic and necrotic injury to hepatocytes by compromising hepatocyte cell membranes and organelles. Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions

Frank Anania, MD, FACP, AGAF Gastroenterology 2007 132, 2191-2207DOI: (10.1053/j.gastro.2007.03.055) Copyright © 2007 AGA Institute Terms and Conditions