Hepatoprotection of capsaicin in alcoholic and non-alcoholic fatty liver diseases

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. In the United States, NAFLD and its subtype, nonalcoholic steatohepatitis, affect 30% and 5% of the population, respectively. Considering the ongoing obesity epidemic beginning in childhood, the rise in diabetes, and other factors, the prevalence of NAFLD along with the proportion of those with advanced liver disease is projected to continue to increase. This will have an important impact on public health reflected in health care costs, including impact on the need for liver transplantation, for which nonalcoholic steatohepatitis is already close to becoming the most common indication. NAFLD patients with evidence of nonalcoholic steatohepatitis and advanced fibrosis are at markedly increased risk of adverse outcomes, including overall mortality, and liver-specific morbidity and mortality, respectively. Identification of this cohort of NAFLD patients is paramount, given the associated poorer outcomes, in order to target resources to those who need it most. Various noninvasive tools have been developed in this regard. This review provides an update on the epidemiology, clinical and prognostic features, and diagnostic approach to patients with NAFLD.