Mitochondrial abnormalities in non-alcoholic steatohepatitis

Caldwell, Stephen H.; Swerdlow, Russell H.; Khan, Elaine M.; Iezzoni, Julia C.; Hespenheide, Elizabeth E; Parks, Jason C.; Parker, W. Davis

doi:10.1016/s0168-8278(99)80033-6

Cited by 464 publications

(300 citation statements)

References 34 publications

Supporting

Mentioning

273

Contrasting

Unclassified

Order By: Relevance

“…20 -23 Additionally, fewer MMC identified in the liver specimens of patients with cryptogenic cirrhosis (patients 9 and 10, Table 2) concur with our prior result. 5 This finding supports the absence of the MMC when the disease is burned out and their presence in association with steatosis, although the small sample size of this group prevents formal testing.…”

Section: Discussionsupporting

confidence: 55%

“…Similar abnormalities have been described in Wilson disease, 3 alcoholic steatohepatitis (where they were believed to be markers of early or less severe alcoholrelated injury), 4 and more recently in nonalcoholic fatty liver, where their presence has been correlated indirectly with oxidative stress and their absence noted when cirrhosis develops. 5,6 We previously estimated that megamitochondria with crystalline inclusions (MMC) are seen in 5% to 15% of hepatocytes in nonalcoholic steatohepatitis (NASH) patients and in 5% to 10% of the mitochondria within an afflicted cell. 5,7 Although not invariable, crystalline inclusions typically appear in close association with swollen mitochondria, which may be rounded or elongated.…”

mentioning

confidence: 99%

“…5,6 We previously estimated that megamitochondria with crystalline inclusions (MMC) are seen in 5% to 15% of hepatocytes in nonalcoholic steatohepatitis (NASH) patients and in 5% to 10% of the mitochondria within an afflicted cell. 5,7 Although not invariable, crystalline inclusions typically appear in close association with swollen mitochondria, which may be rounded or elongated. The crystals occur as long parallel strands, which often deform the shape of the mitochondrion.…”

mentioning

confidence: 99%

See 2 more Smart Citations

The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

et al. 2004

View full text Add to dashboard Cite

Megamitochondria with crystalline inclusions (MMC) have been previously described in nonalcoholic fatty liver; however, their distribution within hepatic zones is unknown. We sought to determine this distribution from the core liver biopsy specimens of 31 patients: 8 males and 23 females, age range 21 to 72 years. Twenty-nine showed evidence of nonalcoholic steatohepatitis (NASH) on biopsy with steatosis, inflammation, varying degree of fibrosis, ballooned hepatocytes, and Mallory hyaline, and two patients had cryptogenic cirrhosis thought to represent "burned out" NASH. Identified by transmission electron microscopy, the abundance of MMC was compared between low-stage (fibrosis stages 1 and 2) and high-stage (fibrosis stages 3 and 4) groups and between zones with or without difference in fibrosis stage. Regardless of stage, the MMC were distributed equally in all zones and were abundant similarly in low-and high-stage groups. This abundance did not correlate with the degree of oxidative stress (4-hydroxynonenal staining) or with the abundance of ballooned hepatocytes. Consistent with age as a risk factor for more severe disease, the median age for the low-stage group was significantly lower than that of the high-stage group (P ‫؍‬ .003). In conclusion, in NASH, the MMC seem to be distributed randomly among zones and without variation in abundance, regardless of the fibrosis stage. The exact function of these structures remains to be defined. In this study, their presence did not seem to correlate with the light microscopic injury pattern represented by ballooned hepatocytes or degree of oxidative stress defined by immunostaining for 4-hydroxynonenal. (HEPATOLOGY

show abstract

Section: Discussionsupporting

confidence: 55%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Increased circulating lipids derived from dietary intake and impaired inhibition of lipolysis stimulate lipid oxidation and production of reactive oxygen species, giving rise to lipid peroxidation and damage of mitochondrial proteins and DNA, reduction of oxidative capacity, and subsequent lipid accumulation. 42,43 In support of this contention, patients with NASH exhibit paracrystalline inclusions in megamitochondria, 11,44 increased mitochondrial DNA mutations, 45 and lower respiratory complex activities in the liver. 20 But even obese subjects already may have lower liver ATP resynthesis upon fructose administration.…”

Section: Discussionmentioning

confidence: 90%

Abnormal hepatic energy homeostasis in type 2 diabetes

et al. 2009

View full text Add to dashboard Cite

Increased hepatocellular lipids relate to insulin resistance and are typical for individuals with type 2 diabetes mellitus (T2DM). Steatosis and T2DM have been further associated with impaired muscular adenosine triphosphate (ATP) turnover indicating reduced mitochondrial fitness. Thus, we tested the hypothesis that hepatic energy metabolism could be impaired even in metabolically well-controlled T2DM. We measured hepatic lipid volume fraction (HLVF) and absolute concentrations of ␥ATP, inorganic phosphate (Pi), phosphomonoesters and phosphodiesters using noninvasive 1 H/ 31 P magnetic resonance spectroscopy in individuals with T2DM (58 ؎ 6 years, 27 ؎ 3 kg/m 2 ), and age-matched and body mass index-matched (mCON; 61 ؎ 4 years, 26 ؎ 4 kg/m 2 ) and young lean humans (yCON; 25 ؎ 3 years, 22 ؎ 2 kg/m 2 , P < 0.005, P < 0.05 versus T2DM and mCON). Insulin-mediated whole-body glucose disposal (M) and endogenous glucose production (iEGP) were assessed during euglycemic-hyperinsulinemic clamps. Individuals with T2DM had 26% and 23% lower ␥ATP (1.68 ؎ 0.11; 2.26 ؎ 0.20; 2.20 ؎ 0.09 mmol/L; P < 0.05) than mCON and yCON individuals, respectively. Further, they had 28% and 31% lower Pi than did individuals from the mCON and yCON groups (0.96 ؎ 0.06; 1.33 ؎ 0.13; 1.41 ؎ 0.07 mmol/L; P < 0.05). Phosphomonoesters, phosphodiesters, and liver aminotransferases did not differ between groups. HLVF was not different between those from the T2DM and mCON groups, but higher (P ‫؍‬ 0.002) than in those from the yCON group. T2DM had 13-fold higher iEGP than mCON (P < 0.05). Even after adjustment for HLVF, hepatic ATP and Pi related negatively to hepatic insulin sensitivity (iEGP) (r ‫؍‬ ؊0.665, P ‫؍‬ 0.010, r ‫؍‬ ؊0.680, P ‫؍‬ 0.007) but not to whole-body insulin sensitivity. Conclusion: These data suggest that impaired hepatic energy metabolism and insulin resistance could precede the development of steatosis in individuals with T2DM. (HEPATOLOGY

show abstract

“…55 Damaged mitochondria have been found to accumulate in the hepatocytes in NASH and a possible defect in mitophagy may contribute to progression of liver damage. 56 Autophagy has also been postulated to be involved in activation of hepatic stellate cells (HSC) with consequent deposition of extracellular matrix and liver fibrosis. The postulated mechanisms include its effect on HSC fat stores in from of vitamin A or a direct effect on its differentiation.…”

Section: Autophagy Modulation In Therapy For Liver Diseasesmentioning

confidence: 99%

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Puri

Chandra

2014

Journal of Clinical and Experimental Hepatology

View full text Add to dashboard Cite

Autophagy is a critical intracellular pathway which maintains cellular function by lysosomal degradation of damaged proteins and organelles besides elimination of invading pathogens. Its primary function is to prevent cell death. Autophagy has diverse physiological functions namely; starvation adaptation, prevention of tumorigenesis, energy homeostasis, intracellular quality control and degradation of abnormal intracellular protein aggregates. Understanding the molecular mechanisms of autophagy has given key insights into the pathogenesis of various diseases like Non Alcoholic Steato-Hepatitis, Hepatitis B and C infections, Alpha-1 antitrypsin deficiency and hepatocellular carcinoma. Pharmacological modulation of autophagy may have a therapeutic potential in management of these liver diseases. ( J CLIN EXP HEPATOL 2014;4:51-59) O urobros or Urobros is an ancient symbol depicting a serpent or a dragon eating its own tail, which symbolizes cyclicality in the sense of something recreating itself. In living organisms, cells and intracellular organelles need to be constantly remodeled and renewed. Autophagy is a term derived from Greek terminology for self-eating and signifies the process of cellular selfdigestion in which cytoplasmic components are degraded in lysosomes. Reminiscent of the serpent eating its own tail in the symbol of Ourobros, the cells are able to survive by using autophagy to remove damaged proteins and organelles, eliminate invading microbes and generate nutrients during starvation.After Metchnicoff, a Russian zoologist, first described phagocytosis, the role of lysosomes and autophagy in degrading cytoplasmic components has been elucidated. 1,2 The control of autophagy has been recently delineated by identification of over 30 Autophagy-related (ATG) genes. 3 Autophagy functions to prevent rather than promote cell death. Autophagy has effects of increased cytoprotection, decreased stem cell attrition, decreased oncogenic transformation, decreased dysfunctional mitochondria and decrease in dysfunctional aggregate prone proteins. 4

show abstract

Mitochondrial abnormalities in non-alcoholic steatohepatitis

Cited by 464 publications

References 34 publications

The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

Abnormal hepatic energy homeostasis in type 2 diabetes

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Contact Info

Product

Resources

About