MicroRNAs in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder. Strongly linked to obesity and diabetes, NAFLD has the characteristics of complex diseases with substantial heterogeneity. Accordingly, our ability to predict the risk of advanced NAFLD and provide efficient treatment may improve by a better understanding of the relationship between genotype and phenotype. MicroRNAs (miRNAs) play a major role in the fine-tuning of gene expression and they have recently emerged as novel biomarkers and therapeutic tools in the management of NAFLD. These short non-coding RNA sequences act by partial repression or degradation of targeted mRNAs. Deregulation of miRNAs has been associated with different stages of NAFLD, while their biological role in the pathogenesis remains to be fully understood. Systems biology analyses based on predicted target genes have associated hepatic miRNAs with molecular pathways involved in NAFLD progression such as cholesterol and lipid metabolism, insulin signaling, oxidative stress, inflammation, and pathways of cell survival and proliferation. Moreover, circulating miRNAs have been identified as promising noninvasive biomarkers of NAFLD and linked to disease severity. This rapidly growing field is likely to result in major advances in the pathomechanism, prognostication, and treatment of NAFLD

Mitochondrial recoupling: a novel therapeutic strategy for cancer?

Recent findings link metabolic transformation of cancer cells to aberrant functions of mitochondrial uncoupling proteins (UCPs). By inducing proton leak, UCPs interfere with mitochondrial synthesis of adenosine 5′-triphosphate, which is also a key determinant of glycolytic pathways. In addition, UCP suppress the generation of superoxide, a byproduct of mitochondrial electron transport and a major source of oxidative stress. The near ubiquitous UCP2 becomes highly abundant in some cancers and may advance metabolic reprogramming, further disrupt tumour suppression, and promote chemoresistance. Here we review current evidence to suggest that inhibition of mitochondrial uncoupling may eliminate these responses and reveal novel anti-cancer strategies

Mitochondrial protein p26 BCL2 reduces growth factor requirements of NIH3T3 fibroblasts

The BCL2 (B cell lymphoma/leukemia-2) proto-oncogene encodes a 26-kDa protein that has been localized to the inner mitochondrial membrane and that has been shown to enhance the survival of some types of hematopoietic cells. Here we show that NIH3T3 fibroblasts stably transfected with a BCL2 expression plasmid exhibit reduced dependence on competence-inducing growth factors (platelet-derived growth factor, PDGF; epidermal growth factor, EGF) for initiation of DNA synthesis. The importance of BCL2 for growth factorinduced proliferation of these cells was further confirmed by the useage of BCL2 antisense oligodeoxynucleotides. The mechanisms by which overexpression of p26 BCL2 contributes to fibroblast proliferation are unknown, but do not involve alterations in: (a) the production of inositol triphosphates (IP3), (b) PDGF-induced transient elevations in cytosolic Ca2+ ions, or (c) the activity of protein kinase C enzymes in these transfected cells. The results imply that changes in mitochondrial functions play an important role in the early stages of the cell cycle that render 3T3 cells competent to respond to the serum progression factors that stimulate entry into S-phase.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29195/1/0000249.pd

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

IMPORTANCE: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. OBJECTIVE: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference\u27s association with geographic and temporal factors. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. EXPOSURE: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. RESULTS: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P \u3c .001) or other screening tests (46 [1.0%] P \u3c .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). CONCLUSIONS AND RELEVANCE: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences

Mitochondrial uncoupling in cancer cells: Liabilities and opportunities

Acquisition of the endosymbiotic ancestor of mitochondria was a critical event in eukaryote evolution. Mitochon- dria offered an unparalleled source of metabolic energy through oxidative phosphorylation and allowed the de- velopment of multicellular life. However, as molecular oxygen had become the terminal electron acceptor in most eukaryotic cells, the electron transport chain proved to be the largest intracellular source of superoxide, contributing to macromolecular injury, aging, and cancer. Hence, the ‘contract of endosymbiosis’ represents a compromise between the possibilities and perils of multicellular life. Uncoupling proteins (UCPs), a group of the solute carrier family of transporters, may remove some of the physiologic constraints that link mitochondrial respiration and ATP synthesis by mediating inducible proton leak and limiting oxidative cell injury. This impor- tant property makes UCPs an ancient partner in the metabolic adaptation of cancer cells. Efforts are underway to explore the therapeutic opportunities stemming from the intriguing relationship of UCPs and cancer. This article is part of a Special Issue entitled Respiratory complex I, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux

Novel strategies in the pharmacotherapy of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) affects an estimated one billion people in the world. NAFLD is a spectrum of disease ranging from steatosis to steatohepatitis with variable outcomes that include cirrhosis and hepatocellular carcinoma. Lifestyle adjustment may be sufficient to manage steatosis, but success is difficult to achieve and sustain. In addition, patients with advanced forms of NAFLD or faster rates of progression need more efficient treatment. There is still no approved pharmacotherapy for NAFLD and current options have been limited to the secondary use of drugs developed for the treatment of obesity or diabetes and to hepatoprotective agents for the effect of which the strength of evidence is variable. However, recent advances in pharmaceutical research may soon change the landscape with several promising drug candidates in the pipeline designed to target specific molecular mechanisms implicated in the pathogenesis of NAFLD

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) advanced to cirrhosis is often complicated by clinically significant portal hypertension, which is primarily caused by increased intrahepatic vascular resistance. Liver fibrosis has been identified as a critical determinant of this process. However, there is evidence that portal venous pressure may begin to rise in the earliest stages of NAFLD when fibrosis is far less advanced or absent. The biological and clinical significance of these early changes in sinusoidal homeostasis remains unclear. Experimental and human observations indicate that sinusoidal space restriction due to hepatocellular lipid accumulation and ballooning may impair sinusoidal flow and generate shear stress, increasingly disrupting sinusoidal microcirculation. Sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells are key partners of hepatocytes affected by NAFLD in promoting endothelial dysfunction through enhanced contractility, capillarization, adhesion and entrapment of blood cells, extracellular matrix deposition, and neovascularization. These biomechanical and rheological changes are aggravated by a dysfunctional gut–liver axis and splanchnic vasoregulation, culminating in fibrosis and clinically significant portal hypertension. We may speculate that increased portal venous pressure is an essential element of the pathogenesis across the entire spectrum of NAFLD. Improved methods of noninvasive portal venous pressure monitoring will hopefully give new insights into the pathobiology of NAFLD and help efforts to identify patients at increased risk for adverse outcomes. In addition, novel drug candidates targeting reversible components of aberrant sinusoidal circulation may prevent progression in NAFLD

Uncoupling protein-2 and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has become the most common form of hepatic disorders in the developed world. NAFLD is part of the metabolic syndrome with insulin resistance as a primary underlying derangement. The natural history of NAFLD may extend from simple steatosis over steatohepatitis into cirrhosis and hepatocellular carcinoma. Among numerous factors shaping these transitions, uncoupling protein-2 (UCP2) may theoretically contribute to every stage of this disease. UCP2 is a recently identified fatty acid-responsive mitochondrial inner membrane carrier protein showing wide tissue distribution with a substantially increased presence in fatty liver. The biological functions of UCP2 are not fully elucidated and the greater part of our current knowledge has been obtained from animal experiments. These data suggest a role for UCP2 in lipid metabolism, mitochondrial bioenergetics, oxidative stress, apoptosis, and even carcinogenesis. Available evidence is reviewed and new concepts are considered to appraise the potential role of UCP2 in the pathogenesis of NAFLD

The Impact of Network Medicine in Gastroenterology and Hepatology

In the footsteps of groundbreaking achievements made by biomedical research, another scientific revolution is unfolding. Systems biology draws from the chaos and complexity theory and applies computational models to predict emerging behavior of the interactions between genes, gene products, and environmental factors. Adaptation of systems biology to translational and clinical sciences has been termed network medicine, and is likely to change the way we think about preventing, predicting, diagnosing, and treating complex human diseases. Network medicine finds gene-disease associations by analyzing the unparalleled digital information discovered and created by high-throughput technologies (dubbed as “omics” science) and links genetic variance to clinical disease phenotypes through intermediate organizational levels of life such as the epigenome, transcriptome, proteome, and metabolome. Supported by large reference databases, unprecedented data storage capacity, and innovative computational analysis, network medicine is poised to find links between conditions that were thought to be distinct, uncover shared disease mechanisms and key drivers of the pathogenesis, predict individual disease outcomes and trajectories, identify novel therapeutic applications, and help avoid off-target and undesirable drug effects. Recent advances indicate that these perspectives are increasingly within our reach for understanding and managing complex diseases of the digestive system