Nonalcoholic fatty liver disease (NAFLD) is associated with obesity. Because the health impact of NAFLD depends on whether or not cirrhosis occurs, our goal has been to clarify the mechanisms for NAFLD progression. In NAFLD, cirrhosis rarely develops unless steatosis progresses to steatohepatitis (NASH), but not all individuals with NASH become cirrhotic. We identified obesity-related defects in hepatic innate immunity that mediates the pathogenesis of NASH. Because a pivotal event in the transition from """"""""simple"""""""" NASH to NASH with fibrosis/cirrhosis is hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSC), we developed a unifying hypothesis that might explain inter-individual differences in the susceptibility to MF-HSC accumulation during NASH. We postulate that NAFLD cirrhosis results from fibrogenic repair of hepatic injury, and HYPOTHESIZE that fibrogenic repair involves dysregulated activation of Hedgehog (Hh) signaling that disrupts normal repair-related immune responses. Our hypothesis is based on the following evidence: hepatocyte apoptosis is a key factor that distinguishes NASH from steatosis;hepatocyte death reproducibly triggers regenerative mechanisms;regeneration of chronic fatty liver damage requires expansion/differentiation of progenitors;and the latter processes are regulated by Hedgehog (Hh) ligands produced by cells that accumulate in injured livers, including MF-HSC, immature ductular cells, and NKT cells. Preliminary data suggest Hh-regulated, repair-related mechanisms promote re-accumulation of hepatic NKT cells, switching of hepatic cytokine production from a Th1-predominant to a Th2-predominant profile, and expansion of MF-HSC populations. This is probably important for NAFLD progression because NKT cell accumulation, Th2 polarization of hepatic cytokines, and MF-HSC growth promote fibrosis in other chronic liver diseases. Moreover, inherited (and acquired) differences in two systems that are known to regulate adiposity (i.e., leptin and Hedgehog) may contribute to inter-individual differences in the susceptibility to hepatic fibrosis. During the next funding period, we will determine the significance of Hh-regulated immune mechanisms that influence liver fibrosis, and evaluate if leptin and Hh signaling pathways interact to regulate fibrotic responses to liver injury. The results may expedite development of novel diagnostic tests and treatments for diverse types of obesity-related pathology, including NAFLD.

Public Health Relevance

The results may expedite development of novel diagnostic tests and treatments for diverse types of obesity- related pathology, including NAFLD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Doo, Edward
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Machado, M V; Michelotti, G A; Jewell, M L et al. (2016) Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis 7:e2096
Machado, Mariana Verdelho; Diehl, Anna Mae (2016) Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology 150:1769-77
Chandrashekaran, Varun; Das, Suvarthi; Seth, Ratanesh Kumar et al. (2016) Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta 1862:32-45
Machado, Mariana Verdelho; Kruger, Leandi; Jewell, Mark L et al. (2016) Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model. Dig Dis Sci 61:137-48
Boursier, Jérôme; Mueller, Olaf; Barret, Matthieu et al. (2016) The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology 63:764-75
Verdelho Machado, Mariana; Diehl, Anna Mae (2016) Role of Hedgehog Signaling Pathway in NASH. Int J Mol Sci 17:
Boursier, Jérôme; Barret, Matthieu; Diehl, Anna Mae (2016) Reply. Hepatology 64:994-5
Machado, Mariana Verdelho; Michelotti, Gregory Alexander; Xie, Guanhua et al. (2015) Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS One 10:e0127991
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Seth, Ratanesh Kumar; Das, Suvarthi; Pourhoseini, Sahar et al. (2015) M1 polarization bias and subsequent nonalcoholic steatohepatitis progression is attenuated by nitric oxide donor DETA NONOate via inhibition of CYP2E1-induced oxidative stress in obese mice. J Pharmacol Exp Ther 352:77-89

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