Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.

The findings indicated that pro-inflammatory cytokines may be important indicators of causes, severity of CHF and prognosis among these patients.

Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cell line, AML12, treated with bafilomycin A 1 (lysosomal v-type H +-translocating ATPase inhibitor). Pathway enrichment analysis revealed significant downregulation of gene sets related to peroxisomal biogenesis and peroxisomal lipid oxidation upon lysosomal inhibition. Mechanistically, pharmacological inhibition of lysosomes as well as genetic knockdown of Tfeb led to downregulation of the peroxisomal master regulator PPARA and its coactivator PPARGC1A/PGC1α. Consistently, ectopic induction of PPARA transcriptional activity rescues the effects of lysosomal inhibition on peroxisomal gene expression. Collectively, our results uncover a novel metabolic regulation of peroxisomes by lysosomes via PPARA-PPARGC1A transcriptional signalling.

The present study was designed to test the hypothesis of a circadian variation in circulating levels of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) in women with fibromyalgia syndrome (FMS). Serum levels of IL-6 and TNF-a were measured at 4 h intervals of the day in 50 women with FMS satisfying American College of Rheumatology criteria for FMS (age 36.68 ± 9.89) as well as 50 healthy control women (age 32.82 ± 10.53). Serum TNF-a levels were substantially increased in patients with FMS but showed no circadian variation. In contrast, no difference in the levels of IL-6 was found. Moreover, there was also no circadian variation in both the groups of patients and controls. We conclude that no circadian pattern exists in the circulating levels of serum IL-6 and TNF-a in patients with FMS, although TNF-a levels are found raised in patients with FMS.

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Fibromyalgia syndrome (FMS) patients have disturbed sleep patterns which may lead to altered circadian rhythm in serum cortisol secretion. The aim of this study was to assess circadian changes, if any, in serum cortisol levels in female patients with FMS. Cortisol levels were estimated every 6 h during 24 h period; in 40 female patients satisfying ACR criteria for FMS (Age 36.4 ± 9.9), and 40 healthy females without FMS (Age 33.8 ± 11.1). A significant difference in the night time serum cortisol level was observed among the patients and control groups (patients, 12.9 ± 9.7 controls 5.8 ± 3.0; p < 0.01). However, no significant difference was found in serum cortisol levels in patients and control groups in the morning (patients, 28.4 ± 13.2 controls, 27.6 ± 14.5; p > 0.05), afternoon (patients, 14.4 ± 5.6 controls, 14.0 ± 6.6; p > 0.05) and evening hours (patients, 10.9 ± 5.8 controls, 8.9 ± 3.6; p > 0.05). It could be concluded that there is an abnormality in circadian secretion of cortisol in female FMS patients.

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