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Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP/PPARγ pathways

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Abstract

High-carbohydrate diets (HCD) can induce the occurrence of nonalcoholic fatty liver disease (NAFLD), characterized by dramatic accumulation of hepatic lipid droplets (LDs). However, the potential molecular mechanisms are still largely unknown. In this study, we investigated the role of autophagy in the process of HCD-induced changes of hepatic lipid metabolism, and to examine the process of underlying mechanisms during these molecular contexts. We found that HCD significantly increased hepatic lipid accumulation and activated autophagy. Using primary hepatocytes, we found that HG increased lipid accumulation and stimulated the release of NEFA by autophagy-mediated lipophagy, and that lipophagy significantly alleviated high glucose (HG)-induced lipid accumulation. Oxidative and endoplasmic reticulum (ER) stress pathways played crucial regulatory roles in HG-induced lipophagy activation and HG-induced changes of lipid metabolism. Further investigation found that HG-activated lipophagy and HG-induced changes of lipid metabolism were via enhancing carbohydrate response element-binding protein (ChREBP) DNA binding capacity at PPARγ promoter region, which in turn induced transcriptional activation of the key genes related to lipogenesis and autophagy. The present study, for the first time, revealed the novel mechanism for lipophagy mediating HCD-induced changes of lipid metabolism by oxidative stress and ER stress, and ChREBP/PPARγ pathways. Our study provided innovative evidence for the direct relationship between carbohydrate and lipid metabolism via ChREBP/PPARγ pathway.

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Abbreviations

3-MA:

3-Methyl adenine

4-PBA:

4-Phenylbutyric acid

6PGD:

6-Phosphogluconate dehydrogenase

ACCa:

Acetyl-CoA carboxylase a

ACSL:

Acyl-CoA synthetase long-chain

AO:

Acridine orange

ATF:

Activating transcription factor

ATG:

Autophagy-related gene

BSA:

Bovine serum albumin

CF:

Condition factor

ChREBP:

Carbohydrate response element-binding protein

CPT-1:

Carnitine palmitoyltransferase-1

CQ:

Chloroquine

DCFH2-DA:

2′,7′-Dichlorodihydrofluorescein diacetate

eIF2α:

Eukaryotic translation initiation factor 2α

ERS:

Endoplasmic reticulum stress

FABPL:

Fatty acid-binding protein liver

FAS:

Fatty acid synthase

FBW:

Final mean body weight

FCR:

Feed conversion rate

FFA:

Free fatty acids

FI:

Feed intake

G6PD:

Glucose 6-phosphate dehydrogenase

GLUT:

Glucose transporter

GRP78:

Glucose-regulated protein 78

GSH:

Glutathione

GSSG:

Glutathione disulfide

HCD:

High-carbohydrate diet

H&E:

Hematoxylin and eosin

HG:

High glucose

HSI:

Hepatosomatic index

HSL:

Hormone-sensitive lipase

ICD:

Intermediate carbohydrate diet

ICDH:

Isocitrate dehydrogenase

IRE1α:

Inositol requiring 1α

LCD:

Low-carbohydrate diet

LD:

Lipid droplet

LXR a:

Liver x receptor a

MAP1LC3B:

Microtubule-associated proteins 1A/1B light chain 3B

IBW:

Initial mean body weight

M199:

Medium-199

MDA:

Malondialdehyde

MDC:

Monodansylcadaverine

ME:

Malic enzyme

NAC:

N-acetyl-l-cysteine

NAFLD:

Nonalcoholic fatty liver disease

NEFA:

Nonesterified fatty acid

OD:

Optical density

ORO:

Oil red O

PERK:

Protein kinase R (PKR)-like ER kinase

PPAR:

Peroxisome proliferator-activated receptor

PVDF:

Polyvinylidene difluoride

ROS:

Reactive oxygen species

S.E.M:

Standard error of the mean

SGR:

Specific growth rate

SOD:

Superoxide dismutase

SREBP-1:

Sterol regulatory element-binding proteins-1

TG:

Triglyceride

UPR:

Unfolded protein response

VAI:

Visceral adipose index

VSI:

Viscerosomatic index

WG:

Weight gain

XBP1:

X-box binding protein 1

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Acknowledgements

This work was supported by the National Key R&D Program of China (2018YFD0900400) and Fundamental Research Funds for the Central Universities, China (Grant no. 2662018PY089).

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Authors and Affiliations

  1. Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China

    Tao Zhao, Kun Wu, Yi-Huan Xu, Guang-Hui Chen, Chuan-Chuan Wei & Zhi Luo

  2. Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China

    Zhi Luo

  3. Diabetes and Nutritional Sciences Division, School of Medicine, King’s College London, London, UK

    Christer Hogstrand

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  1. Tao Zhao
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  4. Yi-Huan Xu
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Contributions

ZL and TZ designed the experiments. TZ carried out animal and cell experiments and sample analysis with the help of KW, YHX, GHC, and CCW; TZ, ZL and CH analyzed data; TZ wrote the manuscript, and ZL and CH revised the manuscript. All the authors read and approved the manuscript.

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Correspondence to Zhi Luo.

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Zhao, T., Wu, K., Hogstrand, C. et al. Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP/PPARγ pathways. Cell. Mol. Life Sci. 77, 1987–2003 (2020). https://doi.org/10.1007/s00018-019-03263-6

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