Nonalcoholic Fatty Liver Disease: Pathogenesis and the Role of Antioxidants

Mehta, Kapil; Thiel, David H. Van; Shah, Nikunj; Mobarhan, Sohrab

doi:10.1301/002966402320387224

Cited by 223 publications

(156 citation statements)

References 15 publications

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“…Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease in clinic, and has a spectrum ranging from that of fatty liver alone, usually a benign and non-progressive condition, to nonalcoholic steatohepatitis (NASH), which may progress to liver cirrhosis (Poonawala et al, 2000;Mehta et al, 2002;Bugianesi et al, 2002). But the pathogenesis of NAFLD remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

Zhang

et al. 2006

J. Zhejiang Univ. - Sci. B

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Abstract:Objective: The prevalence of non-alcoholic fatty liver disease (NAFLD) has markedly increased. Insulin resistance has been implicated in the pathogenesis of NAFLD. This study was aimed at observing the relationship between insulin resistance and NAFLD, and evaluating the role of pioglitazone (PGZ) acting as insulin-sensitizing agents in the prevention and treatment of rat fatty liver induced by high fat feeding. Methods: The rats were separated randomly into 6 groups: model group I were fed high fat diet for 8 weeks, PGZ prevention group were given PGZ 4 mg/(kg⋅d) simultaneously, while control group I were fed normal food for 8 weeks; model group II were fed high fat diet for 16 weeks, PGZ treatment group were given PGZ 4 mg/(kg⋅d) orally simultaneous with high fat diet for 8 weeks after high fat feeding for 8 weeks, control group II were fed normal food for 16 weeks. The rats were sacrificed after 8 weeks and 16 weeks respectively. Liver weight, body weight, serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), tumor necrosis factor alpha (TNF-α), fasting blood glucose (FBG), fasting plasma insulin (FINS), HOMA (homeostasis model assessment) insulin resistance index (HOMA-IR), and the liver histology of rats of all groups were assayed. Results: After 8 weeks, the liver in model group I showed typical steatosis, accompanied with mild to moderate lobular inflammatory cell infiltration, liver indexes and serum levels of ALT, AST, ALP, TNF-α were significantly increased (P<0.05) compared with control group I. Whereas, the degree of hepatic injury was attenuated in PGZ prevention group, liver indexes and serum levels of ALT, ALP were significantly decreased (P<0.05) compared with model group I. After 16 weeks, notable steatosis, and lobular inflammation were observed in model group II rat liver, while the degree of hepatic injury was attenuated in the PGZ treatment group. Liver index, serum levels of ALT, AST, ALP, FINS and HOMA-IR were significantly increased (P<0.05) in model group II compared with control group II. Whereas, in PGZ treatment group, serum levels of AST and FINS showed decreasing tendency, liver indexes, serum levels of ALT, ALP, TNF-α and HOMA-IR were significantly decreased compared with model group II. Conclusion: Insulin resistance plays a role in the pathogenesis of NAFLD in rats. Pioglitazone can attenuate insulin resistance and biochemical and histological injury in high fat-induced fatty liver in rats.

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Section: Discussionmentioning

confidence: 99%

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

Zhang

et al. 2006

J. Zhejiang Univ. - Sci. B

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“…Affected individuals typically present with moderate to severe steatosis and lobular inflammation with fibrosis in 70% and cirrhosis in 15% of patients. Since these early studies, it is currently estimated that the prevalence of NAFLD in the general US population is reaching 20% with the more severe form, NASH present in 3% [7,8]. Even more important, may be the fact that NAFLD is present in the pediatric population with prevalence estimated at 2-10% among children and adolescents in the US and Asia [9].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

381

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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“…In support of the latter possibility, MDB-forming diseases are associated with increased levels of oxidative stress, and rapid MDB reinduction in DDC-primed mice can be reversed by pretreatment with the antioxidant S-adenosylmethionine. [16][17][18][19] An important mechanism that cells use to prevent protein misfolding is the up-regulation and utilization of chaperones that associate with newly synthesized or damaged proteins and facilitate their correct folding. 15 Heat shock proteins (Hsp) are the best-studied chaperones and are distributed in different subcellular compartments.…”

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confidence: 99%

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

Strnad¹,

Guo²,

So³

et al. 2008

Hepatology

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The cytoplasmic hepatocyte inclusions, Mallory-Denk bodies (MDBs), are characteristic of several liver disorders, including alcoholic and nonalcoholic steatohepatitis. In mice, MDBs can be induced by long-term feeding with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 3 to 4 months or rapidly reformed in DDC-induced then recovered mice by DDC refeeding or exposure to a wide range of toxins for only 5 to 7 days. The molecular basis for such a rapid reinduction of MDBs is unknown. We hypothesized that protein changes retained after DDC priming contribute to the rapid MDB reappearance and associate with MDB formation in general terms. Two-dimensional differential-in-gel-electrophoresis coupled with mass spectrometry were used to characterize protein changes in livers from the various treatment groups. The alterations were assessed by real-time reverse-transcription polymerase chain reaction and confirmed by immunoblotting. DDC treatment led to pronounced charged isoform changes in several chaperone families, including Hsp25, 60, 70, GRP58, GRP75, and GRP78, which lasted at least for 1 month after discontinuation of DDC feeding, whereas changes in other proteins normalized during recovery. DDC feeding also resulted in altered expression of Hsp72, GRP75, and Hsp25 and in functional impairment of Hsp60 and Hsp70 as determined using a protein complex formation and release assay. The priming toward rapid MDB reinduction lasts for at least 3 months after DDC discontinuation, but becomes weaker after prolonged recovery. MDB reinduction parallels the rapid increase in p62 and Hsp25 levels as well as keratin 8 cross-linking that is normally associated with MDB formation. Conclusion: Persistent posttranslational modifications in chaperone proteins, coupled with protein cross-linking and altered chaperone expression and function likely contribute to the "toxic memory" of DDC-primed mice. We hypothesize that similar changes are important contributors to inclusion body formation in several diseases. (HEPATOLOGY 2008;48:931-942.)

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Nonalcoholic Fatty Liver Disease: Pathogenesis and the Role of Antioxidants

Cited by 223 publications

References 15 publications

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

Research on the protection effect of pioglitazone for non-alcoholic fatty liver disease (NAFLD) in rats

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

“Toxic memory” via chaperone modification is a potential mechanism for rapid mallory-denk body reinduction

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