Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease

Table 1 Histological scoring and staging system for NASH

	Steatosis Macrovesicular	Steatohepatitis		Stages of NASH Fibrosis
		Lobular Inflammation	Ballooning
Definition and score	Large fat droplet with signet cell appearance of hepatocytes	Assessment of inflammatory foci on 200 × field	Swollen hepatocytes	On trichome staining
0	Less than 5%	Less than 2 foci	None	None
1	5% to 33%	2 to 4 foci	Few	Perisinusoidal (zone 3) or periportal 1a-mild, zone 3 1b-moderate, zone 3 1c-portal or periportal
2	33% to 66%	More than 4 foci	Many cells or prominent ballooning	Perisinusoidal (zone 3) and portal/periportal
3	More than 66%	-	-	Bridging
4	-	-	-	Cirrhosis

Table 2 Pathophysiology of insulin resistance

Actions of insulin	Mechanism of action of insulin	Alterations in insulin resistant states	Net metabolic effect
(a) Stimulatory Increases glucose transport: In adipocytes In myocytes	-Insulin binds to its membrane receptor to cause up regulation of GLUT-4 via mediation of IRS-1/2(activated by phosphorylation at tyrosine sites)	-Impaired post receptor signaling involving IRS proteins -Abnormal phosphorylation of IRS-1 makes it inhibitor of the receptor kinase -Activation of IKK-β by free FA and cytokines leads to activation of NF-κB which further inhibits the genes involved in GLUT synthesis	-Hyperglycemia -Decreased glucose utilization as energy source -Reactive hyperinsulinemia
Increases glycogenesis In hepatocytes In myocytes	-By providing the building blocks -Increases expression and activity of glycogen synthase and inhibiting the glycogenolytic enzymes	-Decreased glycogen synthesis	-Hyperglycemia -Decreased postprandial glycogen stores in liver
Increases lipogenesis In adipose tissue In liver (DNL)	-Increases the supply of substrates -Postprandial stimulation of FAS, ACC and SCD1 -Increases supply of free FA in AT	-Further increase in lipogenesis,esp. DNL -Increased delivery of free FA to liver -Decreased oxidation in hepatocytes	-Excessive fat storage in AT and in other tissues (lipotoxicity) -Hepatic steatosis -Increased adiposity
Increases protein synthesis in muscles	-Activates the translational machinery -Activates protein kinase B which activates the protein synthesizing enzymes -In long term exposure increases ribosome in cells	-Decreased protein synthesis	-Sarcopenia
Increases glucose oxidative pathways	-Enhances glycolysis and Kreb's cycle by activating all the key regulator enzymes	-Inhibited -Lipid oxidation preferentially used for energy purposes	-Hyperglycemia -Oxidative stress in hepatocytes
(b) Inhibitory Decreases gluconeogenesis in liver	-Inhibits pyruvate carboxylase, glucose 6 phosphatase and PEP kinase -Shuttles substrates to lipogenesis	-Enhanced gluconeogenesis -Decreased inhibition of keyregulatory enzymes -Activation of AMPK	-Increased hepatic glucose output -Excessive availability of substrates for lipogenesis -Fasting hyperglycemia
Decreases hepatic glucose output	-Decreases gluconeogenesis -Increases glycogen synthesis -Increases oxidation of glucose	-Increased gluconeogenesis -Decreased glycogenesis and oxidative disposal of glucose	-Hyperglycemia
Suppresses lipolysis in adipose tissue	-Suppression of HSL	-Increased rate of free FA release in fasting state in lean and obese -When corrected for body weight in obese, postprandial lipolysis may seem to be normal or even decreased	-Increased plasma free FA both in fasting and post-prandial states(May be due to a mass effect of overall expansion of body fat depots in case of obese) -Increased free FA efflux -Increased VLDL
Decreases apolipoprotein secretion	-Insulin decreases the synthesis and secretion of Apo-B and Apo-C	-Hyperinsulinemia causes further suppression of expression of apolipoprotein genes and also inhibits post translational modifications and secretion -Enhanced synthesis of Apo-B 48 in intestines	-Trapping of TAG inside the liver -Hepatic steatosis -Increased VLDL
Suppresses β oxidation of fatty acids	-Insulin acts via binding to SREBP-1 transcription factor to cause increased expression of ACC-1 leading to generation of FAS substrates for lipogenesis	-Reactive hyperinsulinemia with unrestricted effect on SREBP causes further inhibition of β-oxidation of free FA in hepatocytes mitochondria	-Hepatic steatosis -CYP system over expression and generation of ROS

Hyperinsulinemia and hyperglycemia are two main net metabolic effects of IR. IR also contributes to expansion of NEFA pool and is now alone considered to be responsible for both the hits of 'two hit hypotheses' of NAFLD. IKK-β: Inhibitor of kappaB kinase beta; NF-κB: Nuclear factor-kappa B; FAS: Fatty acyl synthase; ACC: Acyl-CoA carboxylase; SCD: stearoyl-CoA desaturase; PEP: Phosphoenol pyruvate; CYP: Cytochrome P. FA: fatty acids; AT: adipose tissue; HSL: hormone sensitive lipase; SREBP: sterol regulatory element binding protein;IRS:receptor substrate proteins; GLUT: glucose transporter; AMPK: adenosine monophosphate kinase; ROS: reactive oxygen species.

Table 3 Serum factors in obesity and potential mechanisms of NASH

Factors	Increase in obesity	Source: tissue/cells	Basis of increased levels	Role in development of NASH
FFA[199]	41%	Diet Adipose tissue: (adipocytes) visceral/subcutaneous	-Over nutrition -Unopposed peripheral lipolytic activity secondary to IR	-Lipotoxicity -Induce JNK dependent hepatocytes apoptosis -Cause Bax translocation to hepatocyte lysosomes leading to lysosomal degradation and release of cathepsin B -Enhance expression of apoptosis effectors(TNF-α and Fas) -Generation of ROS at ETC of mitochondria -Increase in hepatic lipid peroxidation
TNF-α[152]	28%	Liver: Kupffer cells/macrophages/HSC/hepatocytes Adipose tissue: macrophages in matrix/adipocytes	-Chronic inflammation in adipose tissue with macrophage infiltration -LPS/endotoxins from small bowel overgrowth -Viral infection -Ethanol -Reactive oxygen species	-Receptor mediated mitochondrial injury with release of ROS and caspases -Induction of lipid peroxidation and cell necrosis (intermediation of ceramide) -TNF-α R1 activation leads to Fas induced apoptosis -Causes release of other cytotoxic cytokines(IL-6, TGF-β) from activated Kupffer cells
IL-6[152]	46%	Blood: monocytes/endothelial cells Adipose tissue: subcutaneous/omental Liver: Kupffer cells/HSC/macrophages	-TNF-α mediated activation of Kupffer cells -Pro-inflammatory cytokines release by cells (macrophages) in adipose tissue	-Mediates synthesis of acute phase proteins by hepatocytes -Activates HSC to cause fibrosis and up regulate various genes involved
Leptin[111,112]	4 .2 to 5.8 times	Adipose tissue: mature adipocyte/few matrix cells Liver: activated HSC	-Increased mass of adipose tissue -Chronic inflammatory mediators in adipose tissue -Leptin resistance	-Regulates hepatic fibrosis by activation of HSC(induction of α2 collagen gene) and modulation of Kupffer cell function -Protects HSC from apoptosis and enhances their regeneration -Up regulates profibrogenic TGF-β synthesis
Resistin[161,162]	Non significant	Adipose tissue: visceral/subcutaneous (adipocytes) Blood: monocytes Liver: Kupffer cells	-IL-6 and TNF-α release inadipose tissue secondary to inflammation -Chronic liver injury	-NF-κB mediated activation of HSC and release of pro-inflammatory(MCP, IL-8, TNF-α) and fibrogenic(TGF-β, leptin) cytokines
IL-8[200]	33%	Inflammatory cells in adipose tissue,liver and blood	-Pro-inflammatory cytokines	-Mediates inflammatory response in NASH
PAI-1[201]	3.5 times	Liver: (activated HSC) Adipose tissue: visceral/omental (matrix and adipocytes)	-Locally produced TGF-β and TNF-α	-Inhibits the activation of fibrinolytic plasmin during fibrogenesis
Angiotensinogen[172]	14%	Liver: hepatocytes Adipose tissue: visceral/subcutaneous (adipocytes)	-Hyperinsulinemia of IR -FFA	-Activates HSC to secrete TGF-β to cause fibrosis

FFA: Free fatty acids; JNK: Janus N kinase; ROS: Reactive oxygen species; ETC: Electron transport chain; TNF-α: Tumor necrosis factor-α; HSC: Hepatic stellate cells; IL: Interleukin; TGF-β: Transforming growth factor-β; MCP: Monocyte chemoattractant protein; NF-κB: Nuclear factor-kappa B; PAI-1: Plasminogen activator inhibitor-1; IR: Insulin resistance.