Biochimica et biophysica actaApr 20, 2016

Cholesterol buildup in liver cells affects stress and inflammation caused by a high fat and sugar diet in fatty liver disease

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Both dietary fat and cholesterol may independently promote liver fat accumulation and inflammation in non-alcoholic steatohepatitis.

Accumulation of cholesterol in liver cells is associated with increased stress in the endoplasmic reticulum and activation of inflammation-related pathways.
Mouse models with a high-fat, high-sugar (HFHS) diet show that cholesterol crystals form in the liver, correlating with increased endoplasmic reticulum cholesterol.
Mice lacking specific cholesterol receptors appear protected from the stresses and inflammation associated with cholesterol accumulation.
High cholesterol diets alone can induce liver fat buildup and inflammation independent of endoplasmic reticulum cholesterol levels.
In vitro experiments indicate that increased cellular cholesterol plays a key role in triggering liver fat accumulation and inflammatory responses.

Simplified

Non-alcoholic steatohepatitis (NASH), is the form of non-alcoholic fatty liver disease posing risk to progress into serious long term complications. Human and pre-clinical models implicate cellular cholesterol dysregulation playing important role in its development. Mouse model studies suggest synergism between dietary cholesterol and fat in contributing to NASH but the mechanisms remain poorly understood. Our laboratory previously reported the primary importance of hepatic endoplasmic reticulum cholesterol (ER-Chol) in regulating hepatic ER stress by comparing the responses of wild type, Ldlr-/-xLcat+/+ and Ldlr-/-xLcat-/- mice, to a 2% high cholesterol diet (HCD). Here we further investigated the roles of ER-Chol and ER stress in HFHS diet-induced NASH using the same strains. With HFHS diet feeding, both WT and Ldlr-/-xLcat+/+ accumulate ER-Chol in association with ER stress and inflammasome activation but the Ldlr-/-xLcat-/- mice are protected. By contrast, all three strains accumulate cholesterol crystal, in correlation with ER-Chol, albeit less so in Ldlr-/-xLcat-/- mice. By comparison, HCD feeding per se (i) is sufficient to promote steatosis and activate inflammasomes, and (ii) results in dramatic accumulation of cholesterol crystal which is linked to inflammasome activation in Ldlr-/-xLcat-/- mice, independent of ER-Chol. Our data suggest that both dietary fat and cholesterol each independently promote steatosis, cholesterol crystal accumulation and inflammasome activation through distinct but complementary pathways. In vitro studies using palmitate-induced hepatic steatosis in HepG2 cells confirm the key roles by cellular cholesterol in the induction of steatosis and inflammasome activations. These novel findings provide opportunities for exploring a cellular cholesterol-focused strategy for treatment of NASH.

Full Text

Full text is available at the source.

View Full Text ↗

Cholesterol buildup in liver cells affects stress and inflammation caused by a high fat and sugar diet in fatty liver disease

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief