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Review
. 2020 Aug 28;12(9):2626.
doi: 10.3390/nu12092626.

Involvement of the Autophagy-ER Stress Axis in High Fat/Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease

Xiu Zhou  1   2   3   4 , Sherouk Fouda  4 , Dongli Li  1   2 , Kun Zhang  1   2   3 , Ji-Ming Ye  1   2   4
Affiliations
Review

Involvement of the Autophagy-ER Stress Axis in High Fat/Carbohydrate Diet-Induced Nonalcoholic Fatty Liver Disease

Xiu Zhou et al. Nutrients. .

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease that can progress from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), and even further to liver cirrhosis or liver cancer. Overconsumption of high fat and/or carbohydrate are among the most common lifestyle factors that drive the development and progression of NAFLD. This review evaluates recent reports on the involvement of autophagy and endoplasmic reticulum (ER) stress in the pathogenesis of NAFLD. Here, we reveal a mechanism of an intrinsically linked axis of impaired autophagy and unresolved ER stress that mediates the development and progression of NAFLD resulting from the overconsumption of high fat and/or carbohydrate.

Keywords: autophagy; endoplasmic reticulum (ER) stress; inflammation; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Temporal changes in ER stress associated lipogenesis following mammalian target of rapamycin (mTOR)-coupled autophagy inhibition induced by dietary fructose. However, the activation of mTOR and its downstream p70 S6K and 4EBP1 is parallel with inhibition of autophagy (Atg5, Atg7, LC3II/LC3I and p62) within 2 h of high-fructose feeding. This is followed by increased ER stress (inositol-requiring enzyme 1/X-box binding protein, IRE1/XBP1) (starting from 6 h) and subsequent increase in lipogenesis (acetyl CoA carboxylase (ACC), fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1)) (after 6 h). Diagram redrawn based on [7].
Figure 2
Figure 2
Proposed role of an autophagy-ER stress axis in the pathogenesis of NAFLD. (A) Mechanism of high intake of fructose-induced NAFLD via the autophagy-ER stress based on [7,29,31,37,38,39,45]. (B) Mechanism of high-fat diet-induced NAFLD via the autophagy-ER stress based on [9,29,31,39,44,46,51,52,53,54].
Figure 3
Figure 3
Proposed autophagy-ER stress-inflammation in the pathogenesis of NAFLD induced by overconsumption of dietary fat and fructose. High fat or high fructose consumption can cause excessive lipid accumulation in the liver known as hepatic steatosis. Cholesterol consumption can aggravate hepatic inflammation and fibrosis possibly independent of autophagy and ER stress. Multiple mechanisms are involved in the development and exacerbation of NAFLD including autophagy, endoplasmic reticulum (ER) stress and inflammatory responses. FA: fatty acid. TG: triglyceride.
See this image and copyright information in PMC

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