Endoplasmic Reticulum Stress and Lipophagy in Nonalcoholic Steatohepatitis

Non-Alcoholic Fat Liver Disease (NAFLD) is often a hepatic complication of obese, hyperlipidemia, diabetes and metabolic syndrome, and affects more than one third of general population in the US and 15% in China. It covers a spectrum of fat accumulation-associated disorders, ranging from simple fatty liver, Nonalcoholic Steatohepatitis (NASH), and End-Stage Liver Disease (ESLD). Approximately, one fifth of NAFLD patients will develop NASH, which may further progress to ESLD with various complications. Hepatocellular Carcinoma (HCC) may occur in all stages of NAFLD, and accounts for an increased incidence of HCC in the US. Despite of pandemic prevalence of NAFLD/NASH, etiology-specific treatment has not been available yet, nor is its pathogenesis fully understood. The multi-factorial feature of this disorder dictates the variance in susceptibility, possibility of disease progression and responses to therapeutics, and requires that therapeutics targeting more than single pathway should be developed, and personalized treatment implemented. To reach such goals, the delineation of Endoplasmic Reticulum (ER) stress and lipophagy, two pathophysiologic responses in addition to known pathologic alterations, such as lipotoxicity, oxidant stress, insulin resistance, would allow revealing the molecular basis for NASH initiation and progression, and point to a right direction for new therapeutic development. The present review aims to cover the current understanding of how ER stress and autophagy take a part in the initiation and progression of NASH, and what therapeutic hints exist in deep insights into these two pathophysiologic responses. The ultimate goal is to develop more effective strategies for NASH intervention.