Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that play a crucial role in regulating genes involved in the biogenesis of cholesterol, fatty acids, and triglycerides. As such, they are implicated in several serious liver diseases, including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). SREBPs are subject to regulation by multiple cofactors and critical signaling pathways, making them an important target for therapeutic interventions. In this review, we first introduce the structure and activation of SREBPs, before focusing on their function in liver disease. We examine the mechanisms by which SREBPs regulate lipogenesis, explore how alterations in these processes are associated with liver disease, and evaluate potential therapeutic strategies using small molecules, natural products, or herb extracts that target these pathways. Through this analysis, we provide new insights into the versatility and multitargets of SREBPs as factors in the modulation of different physiological stages of liver disease, highlighting their potential targets for therapeutic treatment.

How benign liver steatosis progresses to non-alcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver and the brain. Using a hyperphagic mouse fed with Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extra-hepatic alterations during NASH-HCC progression as well as regression. Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz), and WT littermates were fed WD or standard chow for 12w for NASH/fibrosis and 24w for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. Foz+WD mice were steatotic within 1-2w, developed NASH by 4w, and grade 3 fibrosis by 12w, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24w and had reduced survival due to cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival and did not develop HCC. Transcriptomic and histological analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, LPS leakage and intestinal inflammation. This led to acute phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed with subsequent predominance by monocyte recruitment. Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH associated HCC, chronic kidney injury, and heart failure.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate genes involved in the biogenesis of cholesterol, fatty acids, and triglycerides. SREBPs are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). We review the mechanisms by which SREBPs regulate lipogenesis, the alterations in these processes associated with liver diseases, and therapeutic strategies to target these pathways.

Background and objectives: Nonagenarians and centenarians (NCs) are an extremely fragile population, particularly in regard to their physical and cognitive function. The aim of this study was to define the neurocognitive profiles among 29 NCs and their 49 younger cohabitants aged 50–75 years from The Cilento Initiative on Aging Outcomes (CIAO) Pilot study in the South of Italy that had provided initial hypotheses regarding positive psychological traits related to exceptional longevity. Materials and Methods: During the home visits, lifestyle information with specific questionnaires, functional autonomy and the neuropsychological Mini Mental Scale Examination (MMSE), and the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) scale were obtained by qualified study personnel. The total blood oxidative capacity was also determined by testing the reactive derivative of oxygen metabolites (d-ROM) and by the Biological Antioxidant Potential (BAP). In all individuals, the APOE genotype determination was also performed. Results: All the subjects in both groups showed high adherence to the Mediterranean Diet. None of the NCs had severe cognitive impairment, and a very low incidence of dementia was found. The data obtained on the Activities ed Instrumental Activities of Daily Living (ADL-IADL) scale showed that the majority of NCs (16/29) were autonomous in daily life activities. The comparative assessment of NCs and cohabitants showed no significant differences in the laboratory assessment of oxidative stress and APOE genotype. Conclusions: In the Cilento Region of Southern Italy, NCs seemed to have good cognitive status when compared to younger cohabitants aging 50–65 years without significant differences in oxidative stress markers or APOE genotype. These results might be related to optimal adherence to the Mediterranean diet, although other lifestyle factors and positive personality traits may also contribute to their healthy aging. Further studies on a larger population should be performed to confirm the results of this pilot study.