The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

Le, Tri H.; Caldwell, Stephen H.; Redick, Jan A.; Sheppard, Bonnie L.; Davis, Christine A.; Arseneau, Kristen O.; Iezzoni, Julia C.; Hespenheide, Elizabeth E; Al‐Osaimi, Abdullah; Peterson, Theresa C.

doi:10.1002/hep.20202

Cited by 114 publications

(59 citation statements)

References 24 publications

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“…Induction of hepatic CYP2E1 promotes oxidative stress and lipid peroxidation [45] and mitochondrial dysfunction leads to reactive oxygen species formation [46] . Moreover, immune responses to lipid peroxidation products may share in NAFLD progression [47,48] .…”

Section: Role Of Oxidative Stressmentioning

confidence: 99%

Non-alcoholic fatty liver disease: The diagnosis and management

El-Kader

Ashmawy

2015

WJH

311

253

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Non-alcoholic fatty liver disease (NAFLD) is now the most frequent chronic liver disease that occurs across all age groups and is recognized to occur in 14%-30% of the general population, representing a serious and growing clinical problem due to the growing prevalence of obesity and overweight. Histologically, it resembles alcoholic liver injury but occurs in patients who deny significant alcohol consumption. NAFLD encompasses a spectrum of conditions, ranging from benign hepatocellular steatosis to inflammatory nonalcoholic steatohepatitis, fibrosis, and cirrhosis. The majority of hepatocellular lipids are stored as triglycerides, but other lipid metabolites, such as free fatty acids, cholesterol, and phospholipids, may also be present and play a role in disease progression. NAFLD is associated with obesity and insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies; however, staging the disease requires a liver biopsy. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and medications appear promising. The aim of this review is to highlight the current information regarding epidemiology, diagnosis, and management of NAFLD as well as new information about pathogenesis, diagnosis and management of this disease.

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Section: Role Of Oxidative Stressmentioning

confidence: 99%

Non-alcoholic fatty liver disease: The diagnosis and management

El-Kader

Ashmawy

2015

WJH

311

253

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“…Megamitochondria (giant mitochondria) are round or needle-shaped, eosinophilic, intracytoplasmic inclusions more commonly observed in hepatocytes with microvesicular steatosis. The are not zonally restricted [82] . Ultrastructural studies have shown that these abnormal mitochondria show loss of cristae, multilamellar membranes, and paracrystalline inclusions [82,83] .…”

Section: Adult Nashmentioning

confidence: 99%

“…The are not zonally restricted [82] . Ultrastructural studies have shown that these abnormal mitochondria show loss of cristae, multilamellar membranes, and paracrystalline inclusions [82,83] . Megamitochondria in NASH may be the result of injury from lipid peroxidation or represent an adaptive change [84] .…”

Section: Adult Nashmentioning

confidence: 99%

Histopathology of Non-Alcoholic Fatty Liver Disease

Brunt

2009

Clinics in Liver Disease

114

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Histological analysis of liver biopsies remains a standard against which other methods of assessment for the presence and amount of hepatic injury due to nonalcoholic fatty liver disease (NAFLD) are measured. Histological evaluation remains the sole method of distinguishing steatosis from advanced forms of NAFLD, i.e. nonalcoholic steatohepatitis (NASH) and fibrosis. Included in the lesions of NAFLD are steatosis, lobular and portal inflammation, hepatocyte injury in the forms of ballooning and apoptosis, and fibrosis. However, patterns of these lesions are as distinguishing as the lesions themselves. Liver injury in adults and children due to NAFLD may have different histological patterns. In this review, the rationale for liver biopsy, as well as the histopathological lesions, the microscopically observable patterns of injury, and the differential diagnoses of NAFLD and NASH are discussed.

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“…Epidemiologic data have identified hepatic steatosis as a major accelerating factor of hepatocarcinogenesis in chronic HCV-infected patients (11). Moreover, increases in ROS production that can cause oxidative DNA damage, mitochondrial abnormalities, and accelerated hepatocyte proliferation were observed in the steatotic livers (12)(13)(14). Thus, an intriguing possibility has emerged that alteration of fatty acid metabolism in hepatocytes may be central to the pathogenesis of HCC induced by HCV core protein.…”

Section: Introductionmentioning

confidence: 99%

PPARα activation is essential for HCV core protein–induced hepatic steatosis and hepatocellular carcinoma in mice

Tanaka¹,

Moriya²,

Kiyosawa³

et al. 2008

J. Clin. Invest.

167

191

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Transgenic mice expressing HCV core protein develop hepatic steatosis and hepatocellular carcinoma (HCC), but the mechanism underlying this process remains unclear. Because PPARα is a central regulator of triglyceride homeostasis and mediates hepatocarcinogenesis in rodents, we determined whether PPARα contributes to HCV core protein-induced diseases. We generated PPARα-homozygous, -heterozygous, and -null mice with liver-specific transgenic expression of the core protein gene (Ppara +/+ :HCVcpTg, Ppara +/-:HCVcpTg, and Ppara -/-:HCVcpTg mice. Severe steatosis was unexpectedly observed only in Ppara +/+ :HCVcpTg mice, which resulted from enhanced fatty acid uptake and decreased mitochondrial β-oxidation due to breakdown of mitochondrial outer membranes. Interestingly, HCC developed in approximately 35% of 24-month-old Ppara +/+ : HCVcpTg mice, but tumors were not observed in the other genotypes. These phenomena were found to be closely associated with sustained PPARα activation. In Ppara +/-:HCVcpTg mice, PPARα activation and the related changes did not occur despite the presence of a functional Ppara allele. However, long-term treatment of these mice with clofibrate, a PPARα activator, induced HCC with mitochondrial abnormalities and hepatic steatosis. Thus, our results indicate that persistent activation of PPARα is essential for the pathogenesis of hepatic steatosis and HCC induced by HCV infection. IntroductionHCV is one of the major causes of chronic hepatitis, whereas patients with persistent HCV infection have a high incidence of hepatocellular carcinoma (HCC) (1, 2). Occurrence of HCC associated with chronic HCV infection has increased over the past 2 decades (3-5), and chronic HCV infection is recognized as a serious debilitating disease. However, the mechanism in which chronic HCV infection mediates hepatocarcinogenesis remains unclear.HCV core protein was shown to have oncogenic potential (6). To examine how HCV core protein participates in HCV-related hepatocarcinogenesis, transgenic mouse lines were established in which HCV core protein is expressed constitutively in liver at cellular levels similar to those found in chronic HCV-infected patients (7). These mice exhibited hepatic steatosis (7) and insulin resistance (8) as early as 3 months of age; on further aging, these symptoms worsened and hepatic adenomas developed in approximately 30% of mice between 16 and 18 months of age (9). Finally, HCC was found within hepatic adenomas in a classic "nodule-in-nodule" pathology (9). Interestingly, no hepatic inflammation or fibrosis was found in these mice throughout

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The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

Cited by 114 publications

References 24 publications

Non-alcoholic fatty liver disease: The diagnosis and management

Non-alcoholic fatty liver disease: The diagnosis and management

Histopathology of Non-Alcoholic Fatty Liver Disease

PPARα activation is essential for HCV core protein–induced hepatic steatosis and hepatocellular carcinoma in mice

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