Pathogenesis of Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH, because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound-healing responses induced by lipotoxic hepatocytes. Differences in these wound-healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH.

Up-regulated HOTAIR induced by fatty acids inhibits PTEN expression and increases triglycerides accumulation in HepG2 cells

“…NAFLD occurs when triglycerides accumulate in the liver [3,7]. When obesity causes triglycerides failure to be stored in the adipose tissue, triglycerides are transformed into FFAs that are transported to nonadipose tissues [26].…”

“…Metabolic dysfunction of elevated fatty acid synthesis is associated with NAFLD. The extent of triglyceride accumulation is the basis for grading the severity of steatosis in NAFLD [3]. The prevalence of NAFLD increases with increasing body mass index (BMI) [4] and its incidence is increasing each year [5,6].…”

NAFLD therapy and monitoring disease progression

“…However, some of the other of lipids that accumulate in fatty livers (e.g., fatty acids, diacylglycerol, oxysterols,cholesterol, and phospholipids) can cause hepatocyte injury. 20 These lipids can cause hepatocyte damage by mitochondrial damage, exacerbating the insulin resistance and hyperinsulinaemia, changes in cell signalling by interacting with transcription factors and innate immune receptors (toll-like receptors). This lipotoxicity results in endoplasmic reticulum stress, impaired autophagy and sterile inflammation that can potentiate cell injury and death.…”

“…This lipotoxicity results in endoplasmic reticulum stress, impaired autophagy and sterile inflammation that can potentiate cell injury and death. 20 This lipotoxicity caused by lipids other than TG may initiate NASH. Under conditions of energy excess, adipose tissue produces adipocytokines that prevent adipocytes from assimilating FFAs and promote release of FFAs from adipose deposits.…”

“…NASH occurs because lipotoxic hepatocytes release factors that initiate wound-healing responses to the dying hepatocytes. 20 Role of multiple processes acting in tandem is reflected by the lack of an effect of IR-reducing medications on NAFLD. Hence, treatment approaches beyond focusing on insulin resistance might be important.…”