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Dietary protein insufficiency: an important consideration in fatty liver disease?

  • Isaac Ampong (a1), Adam Watkins (a2), Jorge Gutierrez-Merino (a1), John Ikwuobe (a3) and Helen R. Griffiths (a1)...


Dietary protein insufficiency has been linked to excessive TAG storage and non-alcoholic fatty liver disease (NAFLD) in developing countries. Hepatic TAG accumulation following a low-protein diet may be due to altered peroxisomal, mitochondrial and gut microbiota function. Hepatic peroxisomes and mitochondria normally mediate metabolism of nutrients to provide energy and substrates for lipogenesis. Peroxisome biogenesis and activities can be modulated by odd-chain fatty acids (OCFA) and SCFA that are derived from gut bacteria, for example, propionate and butyrate. Also produced during amino acid metabolism by peroxisomes and mitochondria, propionate and butyrate concentrations correlate inversely with risk of obesity, insulin resistance and NAFLD. In this horizon-scanning review, we have compiled available evidence on the effects of protein malnutrition on OCFA production, arising from loss in mitochondrial, peroxisomal and gut microbiota function, and its association with lipid accumulation in the liver. The methyl donor amino acid composition of dietary protein is an important contributor to liver function and lipid storage; the presence and abundance of dietary branched-chain amino acids can modulate the composition and metabolic activity of the gut microbiome and, on the other hand, can affect protective OCFA and SCFA production in the liver. In preclinical animal models fed with low-protein diets, specific amino acid supplementation can ameliorate fatty liver disease. The association between low dietary protein intake and fatty liver disease is underexplored and merits further investigation, particularly in vulnerable groups with dietary protein restriction in developing countries.


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*Corresponding author: Helen R. Griffiths, email


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1.Younossi, ZM, Koenig, AB, Abdelatif, D, et al. (2016) Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 7384.
2.Sattar, N, Forrest, E & Preiss, D (2014) Non-alcoholic fatty liver disease. BMJ 349, g4596.
3.Chiu, S, Sievenpiper, JL, de Souza, RJ, et al. (2014) Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 68, 416.
4.Wang, J, Cao, M, Zhuo, Y, et al. (2016) Catch-up growth following food restriction exacerbates adulthood glucose intolerance in pigs exposed to intrauterine undernutrition. Nutrition 32, 12751284.
5.Haro, D, Marrero, PF, Relat, J, et al. (2019) Nutritional regulation of gene expression: carbohydrate-, fat- and amino acid-dependent modulation of transcriptional activity. Int J Mol Sci 20, E1386.
6.Guo, F & Cavener, DR (2007) The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5, 103114.
7.Montagner, A, Polizzi, A, Fouché, E, et al. (2016) Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut 65, 12021214.
8.Bjørndal, B, Berge, C, Ramsvik, MS, et al. (2013) A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation. Lipids Health Dis 12, 143.
9.Mayneris-Perxachs, J, Bolick, DT, Leng, J, et al. (2016) Protein- and zinc-deficient diets modulate the murine microbiome and metabolic phenotype. Am J Clin Nutr 104, 12531262.
10.Houghton, D, Stewart, C, Day, C, et al. (2016) Gut microbiota and lifestyle interventions in NAFLD. Int J Mol Sci 17, 447.
11.Ipsen, DH, Lykkesfeldt, J & Tveden-Nyborg, P (2018) Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 75, 33133327.
12.Falcon, A, Doege, H, Fluitt, A, et al. (2010) FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am J Physiol-Endocrinol Metab 299, E384E393.
13.Doege, H, Baillie, RA, Ortegon, AM, et al. (2006) Targeted deletion of FATP5 reveals multiple functions in liver metabolism: alterations in hepatic lipid homeostasis. Gastroenterology 130, 12451258.
14.Qiu, Y, Liu, S, Chen, HT, et al. (2013). Upregulation of caveolin-1 and SR-B1 in mice with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int 12, 630636.
15.Asterholm, I, Mundy, WDI, Weng, J, et al. (2012). Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell Metab 15, 171185.
16.Li, M, Chen, D, Huang, H, et al. (2017). Caveolin1 protects against diet induced hepatic lipid accumulation in mice. PLOS ONE 12, e0178748.
17.Miquilena-Colina, ME, Lima-Cabello, E, Sánchez-Campos, S, et al. (2011) Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 60, 1394–402.
18.Wilson, CG, Tran, JL, Erion, DM, et al. (2015) Hepatocyte-specific disruption of CD36 attenuates fatty liver and improves insulin sensitivity in HFD-fed mice. Endocrinology 157, 570585.
19.Martin, GG, Atshaves, BP, Landrock, KK, et al. (2015) Loss of l-FABP, SCP-2/SCP-x, or both induces hepatic lipid accumulation in female mice. Arch Biochem Biophys 580, 4149.
20.Nassir, F & Ibdah, J (2014) Role of mitochondria in nonalcoholic fatty liver disease. Int J Mol Sci 15, 87138742.
21.Begriche, K, Igoudjil, A, Pessayre, D, et al. (2016) Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6, 128.
22.Koliaki, C, Szendroedi, J, Kaul, K, et al. (2015) Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab 21, 739746.
23.Pérez-Carreras, M, Del Hoyo, P, Martín, MA, et al. (2003) Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology 38, 9991007.
24.Simões, IC, Fontes, A, Pinton, P, et al. (2018) Mitochondria in non-alcoholic fatty liver disease. Int J Biochem Cell Biol 95, 9399.
25.Koliaki, C, Szendroedi, J, Kaul, K, et al. (2015) Adaptation of hepatic mitochondrial function in humans with nonalcoholic fatty liver is lost in steatohepatitis. Cell Metab 21, 739746.
26.Williams, B, Correnti, J, Oranu, A, et al. (2017) A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis. FASEB J 32, 130142.
27.Kuwahata, M, Kubota, H, Amano, S, et al. (2011). Dietary medium-chain triglycerides attenuate hepatic lipid deposition in growing rats with protein malnutrition. J Nutr Sci Vitaminol 57, 138143.
28.Contreras, AV, Torres, N & Tovar, AR (2013) PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 4, 439452.
29.Holeček, M (2018) Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab 15, 33.
30.She, P, Van Horn, C, Reid, T, et al. (2007) Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol-Endocrinol Metab 293, E1552E1563.
31.Goffredo, M, Santoro, N, Trico, D, et al. (2017) A branched-chain amino acid-related metabolic signature characterizes obese adolescents with non-alcoholic fatty liver disease. Nutrients 9, E642.
32.Herman, MA, She, P, Peroni, OD, et al. (2010) Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem 285, 1134811356.
33.White, PJ, McGarrah, RW, Grimsrud, PA, et al. (2018) The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metab 27, 12811293.
34.Crown, SB, Marze, N & Antoniewicz, MR (2015) Catabolism of branched chain amino acids contributes significantly to synthesis of odd-chain and even-chain fatty acids in 3T3-L1 adipocytes. PLOS ONE 10, e0145850e0145850.
35.Jenkins, B, West, JA & Koulman, A (2015) A review of odd-chain fatty acid metabolism and the role of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) in health and disease. Molecules 20, 24252444.
36.Wanders, RJ (2014) Metabolic functions of peroxisomes in health and disease. Biochimie 98, 3644.
37.Smith, JJ & Aitchison, JD (2013) Peroxisomes take shape. Nat Rev Mol Cell Biol 14, 803.
38.Walker, CL, Pomatto, LCD, Tripathi, DN, et al. (2018) Redox regulation of homeostasis and proteostasis in peroxisomes. Physiol Rev 98, 89115.
39.Jenkins, B, de Schryver, E, Van Veldhoven, PP, et al. (2017). Peroxisomal 2-hydroxyacyl-CoA lyase is involved in endogenous biosynthesis of heptadecanoic acid. Molecules 22, E1718.
40.van Zutphen, T, Ciapaite, J, Bloks, VW, et al. (2016) Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction. J Hepatol 65, 11981208.
41.Yoo, W, Gjuka, D, Stevenson, HL, et al. (2017) Fatty acids in non-alcoholic steatohepatitis: focus on pentadecanoic acid. PLOS ONE 12, e0189965.
42.Pfeuffer, M & Jaudszus, A (2016) Pentadecanoic and heptadecanoic acids: multifaceted odd-chain fatty acids. Adv Nutr 7, 730734.
43.Al-Lahham, SH, Peppelenbosch, MP, Roelofsen, H, et al. (2010) Biological effects of propionic acid in humans; metabolism, potential applications and underlying mechanisms. Biochim Biophys Acta 1801, 11751183.
44.Comhair, TM, Garcia Caraballo, SC, Dejong, CHC, et al. (2017) The odd-carbon medium-chain fatty triglyceride triheptanoin does not reduce hepatic steatosis. Clin Nutr 36, 229237.
45.Jenkins, B, Aoun, M, Feillet-Coudray, C, et al. (2018) The dietary total-fat content affects the in vivo circulating C15:0 and C17:0 fatty acid levels independently. Nutrients 10, E1646.
46.Wu, Z, Puigserver, P, Andersson, U, et al. (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115124.
47.Mandard, S, Müller, M & Kersten, S (2004) Peroxisome proliferator-activated receptor α target genes. Cell Mol Life Sci 61, 393416.
48.Ghosh, TS, Gupta, SS, Bhattacharya, T, et al. (2014) Gut microbiomes of Indian children of varying nutritional status. PLOS ONE 9, e95547.
49.Kang, W, Lee, MS & Baik, M (2011) Dietary protein restriction alters lipid metabolism and insulin sensitivity in rats. Asian-Australas J Anim Sci 24, 12741281.
50.Kwon, DH, Kang, W, Nam, YS, et al. (2012) Dietary protein restriction induces steatohepatitis and alters leptin/signal transducers and activators of transcription 3 signaling in lactating rats. J Nutr Biochem 23, 791799.
51.Huang, X, Hancock, DP, Gosby, AK, et al. (2013) Effects of dietary protein to carbohydrate balance on energy intake, fat storage, and heat production in mice. Obesity 21, 8592.
52.Watkins, AJ & Sinclair, KD (2014) Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice. Am J Physiol Heart Circ Physiol 15, H1444H1452.
53.Ueland, PM (2011) Choline and betaine in health and disease. J Inherit Metab Dis 34, 315.
54.Kulinski, A, Vance, DE & Vance, JE (2004) A choline-deficient diet in mice inhibits neither the CDP-choline pathway for phosphatidylcholine synthesis in hepatocytes nor apolipoprotein B secretion. J Biol Chem 279, 2391623924.
55.Lyall, MJ, Cartier, J, Richards, JA, et al. (2017) Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD. Wellcome Open Res 2, 67.
56.Madeira, MS, Rolo, EA, Lopes, PA, et al. (2018) Betaine and arginine supplementation of low protein diets improves plasma lipids but does not affect hepatic fatty acid composition and related gene expression profiling in pigs. J Sci Food Agric 98, 598608.
57.Pooya, S, Blaise, S, Moreno Garcia, M, et al. (2012) Methyl donor deficiency impairs fatty acid oxidation through PGC-1alpha hypomethylation and decreased ER-alpha, ERR-alpha, and HNF-4alpha in the rat liver. J Hepatol 57, 344351.
58.David, LA, Maurice, CF, Carmody, RN, et al. (2014) Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559.
59.Schnorr, SL, Candela, M, Rampelli, S, et al. (2014) Gut microbiome of the Hadza hunter-gatherers. Nat Commun 5, 3654.
60.Carmody, RN, Gerber, GK, Luevano, JM, Jr, et al. (2015) Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17, 7284.
61.Wu, GD, Chen, J, Hoffmann, C, et al. (2011) Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105108.
62.Smith, MI, Yatsunenko, T, Manary, MJ, et al. (2013) Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548554.
63.Kolodziejczyk, AA, Zheng, D, Shibolet, O, et al. (2019) The role of the microbiome in NAFLD and NASH. EMBO Mol Med 11, e9302.
64.Hoverstad, T & Midtvedt, T (1986) Short-chain fatty acids in germfree mice and rats. J Nutr 116, 17721776.
65.Kimura, I, Ozawa, K, Inoue, D, et al. (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4, 1829.
66.Weng, H, Endo, K, Li, J, et al. (2015) Induction of peroxisomes by butyrate-producing probiotics. PLOS ONE 10, e0117851.
67.Maslowski, KM, Vieira, AT, Ng, A, et al. (2009) Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 12821286.
68.Jenkins, BJ, Seyssel, K, Chiu, S, et al. (2017) Odd chain fatty acids; new insights of the relationship between the gut microbiota, dietary intake, biosynthesis and glucose intolerance. Sci Rep 7, 44845.
69.Russell, WR, Gratz, SW, Duncan, SH, et al. (2011) High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. Am J Clin Nutr 93, 10621072.
70.Li, Q, Lauber, CL, Czarnecki-Maulden, G, et al. (2017) Effects of the dietary protein and carbohydrate ratio on gut microbiomes in dogs of different body conditions. mBio 8, e01703e01716.
71.Zhou, L, Fang, L, Sun, Y, et al. (2016) Effects of the dietary protein level on the microbial composition and metabolomic profile in the hindgut of the pig. Anaerobe 38, 6169.
72.Claesson, MJ, Jeffery, IB, Conde, S, et al. (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178.
73.Budhathoki, S, Sawada, N, Iwasaki, M, et al. (2019) Association of animal and plant protein intake with all-cause and cause-specific mortality. JAMA Intern Med 179, 15091518.
74.Alferink, LJ, Kiefte-de Jong, JC, Erler, NS, et al. (2019) Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam Study. Gut 68, 10881098.
75.Santesso, N, Akl, EA, Bianchi, M, et al. (2012) Effects of higher- versus lower-protein diets on health outcomes: a systematic review and meta-analysis. Eur J Clin Nutr 66, 780788.
76.Rippin, HL, Hutchinson, J, Jewell, J, et al. (2017) Adult nutrient intakes from current national dietary surveys of European populations. Nutrients 9, E1288.
77.Mchiza, ZJ, Steyn, NP, Hill, J, et al. (2015) A review of dietary surveys in the adult South African population from 2000 to 2015. Nutrients 7, 82278250.
78.Sluik, D, Brouwer-Brolsma, EM, Berendsen, AAM, et al. (2019) Protein intake and the incidence of pre-diabetes and diabetes in 4 population-based studies: the PREVIEW project. Am J Clin Nutr 109, 13101318.
79.van Baak, MA, Larsen, TM, Jebb, SA, et al. (2017) Dietary intake of protein from different sources and weight regain, changes in body composition and cardiometabolic risk factors after weight loss: the DIOGenes study. Nutrients 9, E1326.
80.Drummen, M, Dorenbos, E, Vreugdenhil, ACE, et al. (2018) Long-term effects of increased protein intake after weight loss on intrahepatic lipid content and implications for insulin sensitivity: a PREVIEW study. Am J Physiol Endocrinol Metab 315, E885E891.
81.Campmans-Kuijpers, MJ, Sluijs, I, Nöthlings, U, et al. (2015) Isocaloric substitution of carbohydrates with protein: the association with weight change and mortality among patients with type 2 diabetes. Cardiovasc Diabetol 14, 39.
82.Martens, EA, Gatta-Cherifi, B, Gonnissen, HK, et al. (2014) The potential of a high protein-low carbohydrate diet to preserve intrahepatic triglyceride content in healthy humans. PLOS ONE 9, e109617.


Dietary protein insufficiency: an important consideration in fatty liver disease?

  • Isaac Ampong (a1), Adam Watkins (a2), Jorge Gutierrez-Merino (a1), John Ikwuobe (a3) and Helen R. Griffiths (a1)...


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