Production of Elastin-Derived Peptides Contributes to the Development of Nonalcoholic Steatohepatitis.
Béatrice RomierCorinne IvaldiHervé SarteletAndrea HeinzChristian E H SchmelzerRoselyne GarnotelAlexandre GuillotJessica JonquetEric BertinJean-Louis GuéantJean-Marc AlbertoJean-Pierre BronowickiJohanne AmoyelThinhinane HocineLaurent DucaPascal MauriceAmar BennasrouneLaurent MartinyLaurent DebelleVincent DurlachSébastien BlaisePublished in: Diabetes (2018)
Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cancer, hypertension, and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin, or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1β, and TGF-β), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.
Keyphrases
- high fat diet induced
- insulin resistance
- extracellular matrix
- oxidative stress
- metabolic syndrome
- type diabetes
- induced apoptosis
- adipose tissue
- cardiovascular disease
- blood pressure
- poor prognosis
- liver fibrosis
- high fat diet
- electronic health record
- weight loss
- papillary thyroid
- risk factors
- machine learning
- social media
- risk assessment
- genome wide
- gene expression
- deep learning
- soft tissue
- dna methylation
- single cell
- cell proliferation
- liver injury
- human health
- cell cycle arrest
- physical activity
- solid state
- childhood cancer