Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease

Abstract

Background/Aims Liver biopsies from patients with nonalcoholic fatty liver disease (NAFLD) sometimes exhibit non-zonal aggregates of hepatocytes with microvesicular steatosis, but its prevalence and significance are unclear. In this study, we have evaluated the frequency of microvesicular steatosis and assessed its association with histological markers of disease severity in a large sample of NAFLD liver biopsies. Methods Liver biopsies from a large cohort of adults who participated in two studies conducted by the NASH Clinical Research Network (NASH CRN) were included in this cross-sectional study. Liver histology was assessed centrally and various histological features scored in a systematic fashion. The relationship between microvesicular steatosis and various histological features that characterize NAFLD was tested by multiple logistic regression, after controlling for age, gender, race, body mass index, and diabetes. Results Among 1022 liver biopsies included, 102 (10%) had microvesicular steatosis. No demographic differences were noted between patients with or without microvesicular steatosis. The presence of microvesicular steatosis was associated with higher grades of steatosis (p<0.001), ballooning cell injury (p<0.001), presence of Mallory-Denk bodies (p<0.007), presence of megamitochondria (p<0.0001), higher NAS scores (p<0.0001), more advanced fibrosis (p<0.0001) and diagnosis of borderline or definite NASH (p<0.0001). Conclusion Microvesicular steatosis correlates with more advanced histology of NAFLD. Longitudinal studies are needed to address the role of microvesicular steatosis in mediating cellular injury and disease progression in NAFLD.

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling

“…In agreement with upregulation of different components of lipid synthesis and storage pathways, livers of fructose-supplemented mice show a mixture of microvesicular and macrovesicular steatosis, whereas glucose-supplemented mice show exclusive macrovesicular steatosis. Microvesicular steatosis has been linked with hepatocyte ballooning, mitochondrial dysfunction, and more severe NAFLD phenotype (36). Taken together, our data suggest that the difference in fructose-and glucose-induced lipogenesis stems from unique upregulation of a subset of lipogenic pathways, rather than a simple increase in the total amount of lipids.…”

Thrombin promotes diet-induced obesity through fibrin-driven inflammation

“…Fibrin(ogen) deposits in tissues may influence the obese phenotype through several non-mutually exclusive mechanisms. However, our data suggest that a key mechanism of protection from HFD-induced obesity observed in Fibγ 390-396A mice is downcifically associated with the most detrimental manifestations of NAFLD (data not shown) (34). In addition, DE treatment of HFDfed mice provided a significant protection from HFD-induced increase in blood glucose levels (Table 3).…”

Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease

“…5,[39][40][41] Different mechanisms could explain higher ROS generation during NAFLD: (1) Induction of CYP2E1, 39,42 a ROS-producing enzyme located within the endoplasmic reticulum (ER) and mitochondria. 43,44 (2) Enhanced peroxisomal FAO, the first enzymatic step of which produces H 2 O 2 . 5,45 (3) Higher mtFAO, which is also able to generate ROS, possibly at the level of electron transfer flavoprotein-ubiquinone oxidoreductase, 46,47 or downstream within the MRC.…”

“…In addition to macrovacuolar steatosis, NASH is characterized by microvesicular steatosis, inflammation, fibrosis, and the presence of hepatocyte injury in the forms of ballooning and apoptosis. 1,2 Even though NASH is not by itself a severe hepatic lesion, it can progress to cirrhosis and liver cancer. 3 Collectively, the large spectrum of conditions ranging from fatty liver to NASH is referred to as nonalcoholic liver disease (NAFLD).…”

“…In order to better assess the histological changes in NAFLD, in particular during therapeutic trials, the Pathology Committee of the NASH Clinical Research Network designed and validated the NAFLD activity score (NAS) system, derived from the sum of individual scores for steatosis, lobular inflammation, and hepatocellular ballooning. 2,4 Abbreviations: 4-HNE, 4-hydroxynonenal; ACC, acetyl-CoA carboxylase; AdipoR, adiponectin receptor; ADP, adenosine diphosphate; ANT, adenine nucleotide translocator; ATP, adenosine triphosphate; ChREBP, carbohydrate responsive element-binding protein; CoA, coenzyme A; COX, cytochrome c oxidase; CPT1; carnitine palmitoyltransferase 1; CYP2E1; cytochrome P450 2E1; DNL, de novo lipogenesis; ER: endoplasmic reticulum; FA, fatty acid; FAD, flavin adenine dinucleotide; FAO, fatty acid oxidation; FGF21, fibroblast growth factor 21; FoxO1, forkhead box O1 transcription factor; GSH, reduced glutathione; HFD, high-fat diet; HIF-1a, hypoxia inducible factor-1 alpha; IL6, interleukin 6; iNOS, inducible nitric oxide synthase; IR, insulin resistance; KB, ketone bodies; KICA, ketoisocaproic acid; LCFA, long-chain fatty acid; MCAD, medium-chain acyl-CoA dehydrogenase; MCD, methionine/choline deficient; MCFA, mediumchain fatty acid; MnSOD, manganese superoxide dismutase; MRC, mitochondrial respiratory chain; mtDNA, mitochondrial DNA; mtFAO, mitochondrial FAO; mtGSH, mitochondrial GSH; NAD þ , nicotinamide adenine dinucleotide; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NEFA, nonesterified fatty acid; NO, nitric oxide; OXPHOS, oxidative phosphorylation; PGC1a, PPARa coactivator 1alpha; PPARa, peroxisome proliferator-activated receptor alpha; RNS, reactive nitrogen species; ROS, reactive oxygen species; SCFA, short-chain fatty acid; SREBP1c, sterol regulatory element-binding protein 1c; TAG, triacylglycerol; TCA, tricarboxylic acid; TNF-a, tumor necrosis factor alpha; UCP2, uncoupling protein 2; VLDL, very low density lipoprotein; WAT, white adipose tissue.…”